Pyridino and pyrimidino pyrazinones

ABSTRACT

The present invention provides compounds of Formula I:  
                 
 
     wherein the variables A, B, Ar, R 1 , R 2 , and R 3  are as defined herein. The compounds of Formula (I) can function as corticotropin releasing factor (CRF) receptor antagonists and can be useful, for example, in the treatment of disorders characterized by abnormal levels of CRF such as anxiety and depression.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority of U.S. Provisional Application Serial No. 60/414,853, filed Sep. 30, 2002, the disclosure of which is incorporated herein by reference in its entirety for all purposes.

FIELD OF THE INVENTION

[0002] The present invention provides pyridino and pyrimidino pyrazinone compounds useful as corticotropin releasing factor (CRF) receptor antagonists for the treatment of disorders characterized by physiologically abnormal levels of CRF.

BACKGROUND OF THE INVENTION

[0003] Corticotropin releasing factor (CRF), synonymous with corticotropin releasing hormone (CRH), is a 41 amino acid peptide that coordinates the overall response of the body to stress. As an agonist of CRF receptors (e.g., CRF₁ and CRF₂), CRF is well known as the primary physiological secretagogue controlling hypothalamic-pituitary-adrenal (HPA) axis activity which mediates the endocrine stress response. CRF also plays a central role in the autonomic and behavioral responses to stress. Variation in physiological levels of CRF has been correlated with various disorders including depression, anxiety, and irritable bowel syndrome.

[0004] Antagonists of CRF receptors have been shown to effectively ameliorate behavioral stress responses in animal models. It is well established that systemic administration of CRF₁ receptor antagonists leads to anxiolytic and antidepressant effects in rodents. Animal model evidence also shows that CRF₁ antagonists can help alleviate the symptoms of drug withdrawal, stress-induced seizures, and certain inflammations. A role for CRF has also been postulated in the etiology and pathophysiology of Alzheimer's disease, Parkinson's disease, Huntington's disease, progressive supranuclear palsy, and amyotrophic lateral sclerosis as they relate to the dysfunction of CRF neurons in the central nervous system. Eating disorders, such as anorexia nervosa, have also been linked to elevated levels of CRF.

[0005] Though widely dispersed throughout the central nervous system, CRF receptors are also found in peripheral systems including glandular, vascular, gastrointestinal, and immune system tissues. Accordingly, CRF antagonists are believed to have potential in treating numerous disorders of the peripheral systems. Some CRF-related disorders of peripheral systems include, for example, hypertension, tachycardia, congestive heart failure, stroke, irritable bowel syndrome, post-operative ileus, and colonic hypersensitivity. Studies have indicated that CRF₁ antagonists may also be useful as hair growth stimulators.

[0006] Numerous articles have reported the physiological role of CRF and the potential therapeutic activity of non-peptidic CRF receptor antagonists. Some of these articles, detailing much of the above discussion, include, for example; Gilligan, et al., J. Medicinal Chem., 2000, 43, 1641, Newport, et al., Curr. Opin. Neurobiology, 2000, 10, 211; Mastorakos, et al., Ann. N.Y. Acad. Sci., 2000, 900, 95; Koob, et al., Ann. N.Y. Acad. Sci., 2000, 909, 170; Maillot, et al., Gastroenterology, 2000, 119, 1569; Chrousos, Int. J. Obesity, 2000, 24, Suppl. 2, S50; Owens, et al., Exp. Opin. Invest. Drugs, 1999, 8, 1849; McCarthy, et al., Current Pharmaceutical Design, 1999, 5, 289; Heinrichs, et al., Baillier's Clinical Endocrinology and Metabolism, 1999, 13, 541; Arborelius, et al., Journal of Endocrinology, 1999, 160, 1; Webster, et al., Ann. N.Y. Acad. Sci., 1998, 840, 21; and Chalmers, et al., TiPS, 1996, 17, 166; De Souza, Hosp. Practice, 1988, 23, 59; WO 02/19975; and U.S. Pat. No. 5,236,901, each of which is incorporated herein by reference in its entirety.

[0007] Separate from the compounds reported herein, some pyrimidino pyrazinone-based compounds have been reported in WO 01/62758 as kinase inhibitors and WO 01/19825 for the treatment of chemokine mediated diseases.

[0008] As evidenced by the numerous publications directed to the study of CRF and its connection with various disorders, there is a current need for new ways in which to reduce the effects of abnormal levels of CRF or CRF receptors. For example, treatment methods for alleviating or reducing the physiological and/or neurological symptoms associated with elevated levels of CRF are desirable. The compounds described herein help fulfill these and other needs.

SUMMARY OF THE INVENTION

[0009] The present invention provides compounds of Formula (I):

[0010] or pharmaceutically acceptable salt form thereof, or prodrug form thereof, or radiolabeled form thereof, wherein the variables A, B, Ar, R¹, R², and R³ are as defined herein below. The compounds of Formula (I) can have CRF₁ receptor antagonist activity and therefore can be useful in various methods including the treatment of disorders characterized by abnormal levels of CRF.

[0011] Accordingly, the present invention provides compositions comprising a compound of Formula (I) and a pharmaceutically acceptable carrier.

[0012] The present invention further provides methods of reducing symptoms caused by elevated levels of corticotropin releasing factor in a mammal comprising administering to the mammal a therapeutically effective amount of a compound Formula (I).

[0013] The present invention further provides methods of treating stress-related symptoms in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of Formula (I).

[0014] Further provided by the present invention are methods of treating disorders characterized by abnormal levels of corticotropin releasing factor in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of Formula (I).

[0015] In yet further embodiments, methods are provided for the treatment of anxiety, depression, or irritable bowel syndrome in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of Formula (I).

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

[0016] In a first aspect, the present invention provides, inter alia, compounds of Formula (I):

[0017] or a pharmaceutically acceptable salt forms thereof, or prodrug form thereof, or radiolabeled form thereof, wherein:

[0018] A and B are independently CR⁴ or N, with the proviso that at least one of A and B is N;

[0019] Ar is aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted by one or more substituents independently selected from C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, halogen, CN, NO₂, OR⁵, and SR⁵;

[0020] R¹ is H, CN, C₁-C₄ haloalkyl, NR^(1c)R^(1d), NR^(1c)COR^(1b), COR^(1b), CONR^(1c)R^(1d), OR^(1c), SR^(1c), C₁-C₄ alkyl substituted with 0 to 3 R^(1a), C₂-C₄ alkenyl substituted with 0 to 3 R^(1a), C₂-C₄ alkynyl substituted with 0 to 3 R^(1a), C₃-C₆ cycloalkyl substituted with 0 to 3 R^(1a), or C₄-C₈ cycloalkylalkyl substituted with 0 to 3 R^(1a), with the proviso that R¹ is not CH₂X, wherein X is halogen;

[0021] each R^(1a) is, independently at each occurrence, halogen, CN, N₃, NO₂, C₁-C₂ haloalkyl, NR^(1c)R^(1d), NR^(1c)COR^(1b), COR^(1b), OR^(1c), SR^(1c), S(O)R⁸, or S(O)₂R⁸;

[0022] each R^(1b) is, independently at each occurrence, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₃-C₆ cycloalkyl, C₂-C₄ alkenyl, or C₂-C₄ alkynyl;

[0023] each R^(1c) is, independently at each occurrence, selected from H, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₃-C₆ cycloalkyl, C₂-C₄ alkenyl, or C₂-C₄ alkynyl;

[0024] each R^(1d) is, independently at each occurrence, selected from H, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₃-C₆ cycloalkyl, C₂-C₄ alkenyl, or C₂-C₄ alkynyl;

[0025] R² is H, C₁-C₃ haloalkyl, CN, OH, COR^(2b), SH, SR^(2b), SO₂NHR^(2c), SO₂NR^(2c)R^(2d), CONHR^(2c), CONR^(2c)R^(2d), OCOR^(2b), OR^(2b), NR^(2c)R^(2d), CO₂R^(2b), C₁-C₄ alkyl substituted with 0 to 3 R^(2a), C₂-C₄ alkenyl substituted with 0 to 3 R^(2a), C₂-C₄ alkynyl substituted with 0 to 3 R^(2a), or C₃-C₆ cycloalkyl substituted with 0 to 3 R^(2a); with the proviso that R² is not CH₂X, wherein X is halogen;

[0026] each R^(2a) is, independently at each occurrence, halogen, CN, N₃, NO₂, CF₃, OR^(2c), NR^(2c), NR^(2c)R^(2d), NR^(2c)CO₂R^(2b), SR^(2c), SOR⁸, SO₂R⁸, CO₂R^(2b), CONR^(2c)R^(2d), COR^(2b), OCOR^(2b), NR^(2c)CONR^(2c)R^(2d), NR^(2c)CO₂R^(2b), OCONR^(2c)R^(2d), piperidinyl, pyrrolidinyl, piperazinyl, N-methylpiperazinyl, morpholinyl, or thiomorpholinyl;

[0027] each R^(2b) is, independently at each occurrence, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₃-C₆ cycloalkyl, C₄-C₁₂ cycloalkylalkyl, aryl, heteroaryl, aryl-C₁-C₄ alkyl, or heteroaryl-C₁-C₄ alkyl;

[0028] each R^(2c) is, independently at each occurrence, H, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₃-C₆ cycloalkyl, C₄-C₁₂ cycloalkylalkyl aryl, heteroaryl, aryl-C₁-C₄ alkyl, or heteroaryl-C₁-C₄ alkyl;

[0029] each R^(2d) is, independently at each occurrence, H, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₃-C₆ cycloalkyl, C₄-C₁₂ cycloalkylalkyl aryl, heteroaryl, aryl-C₁-C₄ alkyl, or heteroaryl-C₁-C₄ alkyl;

[0030] R³ is OR^(3c), NR^(3c)R^(3d), NHR^(3c), SR^(3c), S(O)R⁸, S(O)₂R⁸, SO₂NHR^(3c), SO₂NR^(3c)R^(3d), COR^(3c), CONHR^(3c), CONR^(3c)R^(3d), aryl substituted with 0 to 3 R^(3a), heteroaryl substituted with 0 to 3 R^(3a), heterocyclyl substituted with 0 to 3 R^(3f), C₁-C₁₀ alkyl substituted with 0 to 3 R^(3a), C₃-C₁₀ alkenyl substituted with 0 to 3 R^(3a), C₃-C₁₀ alkynyl substituted with 0 to 3 R^(3a), C₃-C₈ cycloalkyl substituted with 0 to 3 R^(3a), C₄-C₁₂ cycloalkylalkyl substituted with 0 to 3 R^(3a), C₂-C₁₀ alkoxyalkyl substituted with 0 to 3 R^(3a), C₂-C₁₀ thioalkoxyalkyl substituted with 0 to 3 R^(3a), C₅-C₁₀ cycloalkenyl substituted with 0 to 3 R^(3a), or C₆-C₁₀ cycloalkenylalkyl substituted with 0 to 3 R^(3a), wherein one carbon in any cycloalkyl moiety is optionally replaced with O, S or NR⁵;

[0031] each R^(3a) is, independently at each occurrence, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₆ cycloalkyl, halogen, C₁-C₄ haloalkyl, CN, OR^(3c), SR^(3c), S(O)_(n)R⁸, COR^(3b), NHR^(3c)SO₂R^(3b), OC(O)NR^(3c)R^(3d), N₃, OC(O)OR^(3b), CO₂R^(3c), OC(O)R^(3b), NR^(3c)COR^(3b), N(COR^(3b))₂, NR^(3c)CONR^(3c)R^(3d), NR^(3c)CO₂R^(3b), NR^(3c)R^(3d), CONR^(3c)R^(3d), aryl, heteroaryl, or heterocyclyl;

[0032] each R^(3b) is, independently at each occurrence, C₁-C₁₀ alkyl substituted with 0 to 3 R^(3e), C₂-C₁₀ alkenyl substituted with 0 to 3 R^(3e), C₂-C₁₀ alkynyl substituted with 0 to 3 R^(3e), C₃-C₈ cycloalkyl substituted with 0 to 3 R^(3e), C₄-C₁₂ cycloalkylalkyl substituted with 0 to 3 R^(3e), C₂-C₁₀ alkoxyalkyl substituted with 0 to 3 R^(3e), C₅-C₁₀ cycloalkenyl substituted with 0 to 3 R^(3e), or C₆-C₁₀ cycloalkenylalkyl substituted with 0 to 3 R^(3e), wherein one carbon in any cycloalkyl moiety is optionally replaced with O, S or NR⁵;

[0033] each R^(3c) is, independently at each occurrence, H, C₁-C₁₀ alkyl substituted with 0 to 3 R^(3e), C₂-C₁₀ alkenyl substituted with 0 to 3 R^(3e), C₂-C₁₀ alkynyl substituted with 0 to 3 R^(3e), C₃-C₈ cycloalkyl substituted with 0 to 3 R^(3e), C₄-C₁₂ cycloalkylalkyl substituted with 0 to 3 R^(3e), C₂-C₁₀ alkoxyalkyl substituted with 0 to 3 R^(3e), C₅-C₁₀ cycloalkenyl substituted with 0 to 3 R^(3e), or C₆-C₁₀ cycloalkenylalkyl substituted with 0 to 3 R^(3e), wherein one carbon in any cycloalkyl moiety is optionally replaced with O, S or NR⁵;

[0034] each R^(3d) is, independently at each occurrence, H, C₁-C₁₀ alkyl substituted with 0 to 3 R^(3e), C₂-C₁₀ alkenyl substituted with 0 to 3 R^(3e), C₂-C₁₀ alkynyl substituted with 0 to 3 R^(3e), C₃-C₈ cycloalkyl substituted with 0 to 3 R^(3e), C₄-C₁₂ cycloalkylalkyl substituted with 0 to 3 R^(3e), C₂-C₁₀ alkoxyalkyl substituted with 0 to 3 R^(3e), C₅-C₁₀ cycloalkenyl substituted with 0 to 3 R^(3e), or C₆-C₁₀ cycloalkenylalkyl substituted with 0 to 3 R^(3e), wherein one carbon in any cycloalkyl moiety is optionally replaced with O, S or NR⁵;

[0035] each R^(3e) is, independently at each occurrence, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₁₀ alkynyl, C₃-C₆ cycloalkyl, halogen, C₁-C₄ haloalkyl, CN, OR^(7a), SR^(7a), S(O)_(n)R⁸, COR⁶, CO₂R^(7a), OC(O)R⁶, NR^(7a)COR⁶, N(COR⁶)₂, NR^(7a)CONR^(7a)R^(7b), NR^(7a)CO₂R⁶, NR^(7a)R^(7b), NHR^(7a)SO₂R⁶, OC(O)NR^(7a)R^(7b), N₃, OC(O)OR⁶, CONR^(7a)R^(7b), aryl, heteroaryl, or heterocyclyl;

[0036] each R^(3f) is, independently at each occurrence, oxo, sulfido, or R^(3a);

[0037] R⁴ is H, halogen, CN, C₁-C₃ haloalkyl, COR^(4b), OR^(4c), SR^(4c), SO₂NHR^(4c), SO₂NR^(4c)R^(4d), CONHR^(4c), CONR^(4c)R^(4d), OCOR^(4b), NR^(4c)CONHR^(4c), NR^(4c)CONR^(4c)R^(4d), NR^(4c)CO₂R^(4b), OCONR^(4c)R^(4d), NR^(4c)R^(4d), CO₂R^(4b), C₁-C₄ alkyl substituted with 0 to 1 R^(4a), C₂-C₄ alkenyl substituted with 0 to 1 R^(4a), C₂-C₄ alkynyl substituted with 0 to 1 R^(4a), C₃-C₆ cycloalkyl substituted with 0 to 1 R^(4a), piperidinyl, pyrrolidinyl, piperazinyl, N-methylpiperazinyl, morpholinyl, or thiomorpholinyl;

[0038] each R^(4a) is, independently at each occurrence, halogen, CN, CF₃, OR^(4c), NHR^(4c), NR^(4c)R^(4d), NR^(4c)CO₂R^(4b), SR^(4c), SOR⁸, SO₂R⁸, CO₂R^(4b), CONHR^(4c), CONR^(4c)R^(4d), COR^(4b), OCOR^(4b), NR^(4c)CONR^(4c)R^(4d), NR^(4c)CO₂R^(4b), OCONR^(4c)R^(4d), piperidinyl, pyrrolidinyl, piperazinyl, N-methylpiperazinyl, morpholinyl, or thiomorpholinyl;

[0039] each R^(4b) is, independently at each occurrence, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₃-C₆ cycloalkyl, C₄-C₁₂ cycloalkylalkyl, aryl, heteroaryl, aryl-C₁-C₄ alkyl, or heteroaryl-C₁-C₄ alkyl;

[0040] each R^(4c) is, independently at each occurrence, H, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₃-C₆ cycloalkyl, C₄-C₁₂ cycloalkylalkyl, aryl, heteroaryl, aryl-C₁-C₄ alkyl, or heteroaryl-C₁-C₄ alkyl;

[0041] each R^(4d) is, independently at each occurrence, H, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₃-C₆ cycloalkyl, C₄-C₁₂ cycloalkylalkyl, aryl, heteroaryl, aryl-C₁-C₄ alkyl, or heteroaryl-C₁-C₄ alkyl;

[0042] R⁵ is H, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, or C₂-C₆ alkoxyalkyl;

[0043] R⁶ is, independently at each occurrence, C₁-C₆ alkyl, C₁-C₆ haloalkyl C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₁₂ cycloalkylalkyl, C₂-C₈ alkoxyalkyl, C₅-C₁₂ bis(alkoxy)alkyl, aryl, aryl-C₁-C₄ alkyl, heteroaryl, or heteroaryl-C₁-C₄ alkyl;

[0044] each R^(7a) is, independently at each occurrence, H, C₁-C₆ alkyl, C₁-C₆ haloalkyl C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₁₂ cycloalkylalkyl, C₂-C₈ alkoxyalkyl, C₅-C₁₂ bis(alkoxy)alkyl, aryl, aryl-C₁-C₄ alkyl, heteroaryl, or heteroaryl-C₁-C₄ alkyl;

[0045] each R^(7b) is, independently at each occurrence, H, C₁-C₆ alkyl, C₁-C₆ haloalkyl C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₁₂ cycloalkylalkyl, C₂-C₈ alkoxyalkyl, C₅-C₁₂ bis(alkoxy)alkyl, aryl, aryl-C₁-C₄ alkyl, heteroaryl, or heteroaryl-C₁-C₄ alkyl; and

[0046] R⁸ is C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₃-C₆ cycloalkyl, C₄-C₁₂ cycloalkylalkyl, aryl, heteroaryl, aryl-C₁-C₄ alkyl, or heteroaryl-C₁-C₄ alkyl, or NR^(7a)R^(7b).

[0047] According to some embodiments according to the first aspect, the present invention includes compounds of Formula (I) where A and B are both N. In other embodiments, the present invention includes compounds of Formula (I) wherein one of A and B is CR⁴. For example, the present invention includes compounds of Formula (Ia) and (Ib):

[0048] In some embodiments according to the first aspect, compounds of Formula (I) include those where Ar is aryl. Aryl can be, for example, phenyl substituted with 0 to 5 substituents or naphthyl substituted with 0 to 7 substituents. Example substituents include C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, halogen, CN, NO₂, OR⁵, and SR⁵.

[0049] In other embodiments according to the first aspect, the present invention includes compounds wherein Ar is heteroaryl, including for example, heteroaryl groups having six-membered or five-membered rings. Example heteroaryl groups include pyridyl or pyrimidinyl. In some embodiments, the heteroaryl group is substituted with 0 to 4 substituents such as, for example, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, halogen, CN, NO₂, OR⁵, and SR⁵. Other example heteroaryl groups include oxazolyl, isoxazolyl, or thienyl. According to such embodiments, the heteroaryl group can be substituted with 0 to 4 substituents such as, for example, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, halogen, CN, NO₂, OR⁵, and SR⁵.

[0050] In some embodiments according to the first aspect, the present invention includes compounds of Formula (I) where R¹ is H, CN, OH, C₁-C₄ alkyl, or C₁-C₂ haloalkyl.

[0051] In other embodiments, R¹ can be C₁-C₄ alkyl.

[0052] In further embodiments according to the first aspect, the present invention includes compounds of Formula (I) where R² is H, CN, OH, SH, OR^(2b), SR^(2b), C₁-C₃ haloalkyl, or C₁-C₄ alkyl substituted with 0 to 3 R^(2a). In other embodiments, R² can be H.

[0053] In yet further embodiments according to the first aspect, the present invention includes compounds of Formula (I) where R³, is S(O)R⁸, S(O)₂R⁸, COR^(3c), CONHR^(3c), CONR^(3c)R^(3d), C₁-C₈ alkyl substituted with 0 to 3 R^(3a), C₃-C₈ alkenyl substituted with 0 to 3 R^(3a), C₃-C₈ alkynyl substituted with 0 to 3 R^(3a), C₃-C₆ cycloalkyl substituted with 0 to 3 R^(3a), or C₄-C₁₀ cycloalkylalkyl substituted with 0 to 3 R^(3a). In some embodiments, one carbon in any cycloalkyl moiety can be optionally replaced with O, S or NR⁵.

[0054] According to some embodiments according to the first aspect, compounds of Formula (I) can include those where R³ is C₁-C₆ alkyl substituted with 0 to 2 R^(3a). In yet further embodiments, R^(3a) can be, for example, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, F, Cl, Br, CF₃, CN, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, OR^(3c), SR^(3c), COR^(3b), NHR^(3c)SO₂R^(3b), OC(O)NR^(3c)R^(3d), N₃, OC(O)OR^(3b), CO₂R^(3c), OC(O)R^(3b), NR^(3c)COR^(3b), N(COR^(3b))₂, NR^(3c)CONR^(3c)R^(3d), NR^(3c)CO₂R^(3b), NR^(3c)R^(3d), or CONR^(3c)R^(3d).

[0055] According to further embodiments, the present invention includes compounds of Formula (I) where R⁴ is H, CN, OH, C₁-C₄ alkyl, C₁-C₃ haloalkyl, SR^(4c), or OR^(4c). According to some embodiments, R⁴ can be H.

[0056] In a second aspect, the present invention includes compounds of Formula (I) wherein:

[0057] A is CR⁴ or N;

[0058] Ar is aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted by one or more substituents independently selected from C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, halogen, CN, NO₂, OR⁵, and SR⁵;

[0059] R¹ is H, CN, OH, SH, C₁-C₄ haloalkyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, C₁-C₄ alkyl substituted with 0 to 3 R^(1a), C₂-C₄ alkenyl substituted with 0 to 3 R^(1a), or C₂-C₄ alkynyl substituted with 0 to 3 R^(1a);

[0060] R^(1a) is F, Cl, Br, CN, NO₂, OH, methyl, ethyl, OCH₃, CF₃, CHF₂, or OCF₃;

[0061] R² is H, CN, OH, NR^(2c)R^(2d), C₁-C₃ alkyl substituted with 0 to 3 R^(2a), C₁-C₃ alkoxy, C₁-C₂ haloalkyl, or C₁-C₂ haloalkoxy;

[0062] R³ is SOR⁸, SO₂R⁸, SO₂NR^(3c)R^(3d), COR^(3c), CONHR^(3c), CONR^(3c)R^(3d), aryl substituted with 0 to 3 R^(3a), heteroaryl substituted with 0 to 3 R^(3a), heterocyclyl substituted with 0 to 3 R^(3f), C₁-C₁₀ alkyl substituted with 0 to 3 R^(3a), C₃-C₁₀ alkenyl substituted with 0 to 3 R^(3a), C₃-C₁₀ alkynyl substituted with 0 to 3 R^(3a), C₃-C₈ cycloalkyl substituted with 0 to 3 R^(3a), C₄-C₁₂ cycloalkylalkyl substituted with 0 to 3 R^(3a), C₂-C₁₀ alkoxyalkyl substituted with 0 to 3 R^(3a), C₂-C₁₀ thioalkoxyalkyl substituted with 0 to 3 R^(3a), C₅-C₁₀ cycloalkenyl substituted with 0 to 3 R^(3a), or C₆-C₁₀ cycloalkenylalkyl substituted with 0 to 3 R^(3a), wherein one carbon in any cycloalkyl moiety is optionally replaced with O, S or NR⁵;

[0063] R⁴ is H, halogen, CN, C₁-C₃ haloalkyl, OR^(4c), SR^(4c), NR^(4c)R^(4d), CO₂R^(4b), C₁-C₄ alkyl substituted with 0 to 1 R^(4a), or C₃-C₆ cycloalkyl substituted with 0 to 1 R^(4a);

[0064] each R^(4a) is, independently at each occurrence, halogen, CN, CF₃, OR^(4c), NHR^(4c), NR^(4c)R^(4d), NR^(4c)CO₂R^(4b), SR^(4c), SOR⁸, SO₂R⁸, CO₂R^(4b), CONHR^(4c), CONR^(4c)R^(4d), COR^(4b), OCOR^(4b), NR^(4c)CONR^(4c)R^(4d), NR^(4c)CO₂R^(4b), OCONR^(4c)R^(4d);

[0065] each R^(4b) is, independently at each occurrence, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₃-C₆ cycloalkyl, C₄-C₁₂ cycloalkylalkyl, aryl, heteroaryl, aryl-C₁-C₄ alkyl, or heteroaryl-C₁-C₄ alkyl;

[0066] each R^(4c) is, independently at each occurrence, H, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₃-C₆ cycloalkyl, C₄-C₁₂ cycloalkylalkyl, aryl, heteroaryl, aryl-C₁-C₄ alkyl, or heteroaryl-C₁-C₄ alkyl;

[0067] each R^(4d) is, independently at each occurrence, H, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₃-C₆ cycloalkyl, C₄-C₁₂ cycloalkylalkyl, aryl, heteroaryl, aryl-C₁-C₄ alkyl, or heteroaryl-C₁-C₄ alkyl;

[0068] R⁵ is H, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, or C₂-C₆ alkoxyalkyl;

[0069] each R^(7a) is, independently at each occurrence, H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₄-C₁₂ cycloalkylalkyl, or C₂-C₈ alkoxyalkyl;

[0070] each R^(7b) is, independently at each occurrence, H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₄-C₁₂ cycloalkylalkyl, or C₂-C₈ alkoxyalkyl; and

[0071] R⁸ is C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₃-C₆ cycloalkyl, C₄-C₁₂ cycloalkylalkyl, aryl, heteroaryl, aryl-C₁-C₄ alkyl, or heteroaryl-C₁-C₄ alkyl, or NR^(7a)R^(7b). Remaining variables can be defined as described above in the first aspect of the invention.

[0072] In some embodiments according to the second and first aspects of the invention, A can be N or A can be CR⁴.

[0073] In further embodiments according to the second and first aspects of the invention, R¹ can be H, CN, OH, C₁-C₄ alkyl, or C₁-C₂ haloalkyl.

[0074] In yet further embodiments according to the second and first aspects of the invention, R² can be H, CN, OH, methyl, ethyl, methoxy, OCF₃, CF₃, CHF₂, CH₂CF₃, or CF₂CH₃. In other embodiments, R² can be H.

[0075] In yet further embodiments according to the second and first aspects of the invention, R^(3e), can be C₁-C₆ alkyl substituted with 0 to 2 R^(3a).

[0076] In even further embodiments according to the second and first aspects of the invention, R⁴ can be H, CN, OH, C₁-C₄ alkyl, C₁-C₃ haloalkyl, SR^(4c), or OR⁴. In other embodiments, R⁴ can be H.

[0077] In still further embodiments according to the second and first aspects of the invention, Ar can be aryl. Aryl, can be, for example, phenyl substituted with 0 to 5 substituents or naphthyl substituted with 0 to 7 substituents. Example substituents can be independently selected from C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, halogen, CN, NO₂, OR⁵, and S⁵.

[0078] In other embodiments according to the second and first aspects of the invention, Ar can be heteroaryl, such as for example a six-membered heteroaryl ring or a five-membered heteroaryl ring. Some example heteroaryl groups include pyridyl or pyrimidinyl. These groups can be substituted with 0 to 4 substituents such as, for example, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, halogen, CN, NO₂, OR⁵, and SR⁵. Other example heteroaryl groups include oxazolyl, isoxazolyl, or thienyl. These groups can be substituted with 0 to 4 substituents such as, for example, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, halogen, CN, NO₂, OR⁵, and SR⁵.

[0079] In a third aspect, the present invention includes compounds of Formula (I) wherein:

[0080] A is N or CR⁴;

[0081] Ar is phenyl, pyridyl, pyrimidinyl, oxazolyl, isoxazolyl, or thienyl, wherein the phenyl is substituted with 0 to 5 R^(9a) and the pyridyl, pyrimidinyl, oxazolyl, isoxazolyl, or thienyl is substituted with 0 to 4 R^(9b);

[0082] R¹ is H, CN, methyl, ethyl, methoxy, OH, or C₁-C₂ haloalkyl;

[0083] R² is H, CN, OH, CH₃, OCH₃, CF₃, CHF₂, or OCF₃;

[0084] R³, is S(O)R⁸, S(O)₂R⁸, COR^(3c), CONHR^(3c), CONR^(3c)R^(3d), C₁-C₈ alkyl substituted with 0 to 3 R^(3a), C₃-C₈ alkenyl substituted with 0 to 3 R^(3a), C₃-C₈ alkynyl substituted with 0 to 3 R^(3a), C₃-C₆ cycloalkyl substituted with 0 to 3 R^(3a), or C₄-C₁₀ cycloalkylalkyl substituted with 0 to 3 R^(3a), wherein one carbon in any cycloalkyl moiety is optionally replaced with O, S or NR⁵;

[0085] each R^(3a) is, independently at each occurrence, methyl, ethyl, methoxy, ethoxy, thiomethoxy, thioethoxy, cyclopropyl, cyclobutyl, F, Cl, CF₃ CHF₂, CH₃, or OCF₃;

[0086] R⁴ is H, CHF₂, CF₃, methyl, ethyl, Cl, F, OH, SH, methoxy, thiomethoxy, CH₂CF₃, or CF₂CH₃; and

[0087] each R^(9a) and R^(9b) is, independently at each occurrence, F, Cl, Br, CN, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, isopropoxy, C₁-C₂ haloalkyl, or C₁-C₂ haloalkoxy. Remaining variables can be defined as recited above according to the second aspect of the invention.

[0088] In embodiments according to the first, second, and third aspects, compounds of Formula (I) include those where A is N or A is CR⁴.

[0089] In further embodiments according to the first, second, and third aspects, compounds of Formula (I) include those where R² is H.

[0090] In yet further embodiments according to the first, second, and third aspects, compounds of Formula (I) include those where R³ is butyl, pentyl, hexyl, heptyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, methoxyhexyl, thiomethoxyethyl, thiomethoxypropyl, thiomethoxybutyl, thiomethoxypentyl, thiomethoxyhexyl, 1-cyclopropylpropyl, 1-cyclopropylbutyl, 1-cyclopropylpentyl, 1-cyclobutylpropyl, 1-cyclobutylbutyl, 1-cyclobutylpentyl, 1-cyclopropyl-1-(CF₃)-methyl, 1-cyclopropyl-1-(CF₃)-ethyl, 1-cyclopropyl-1-(CF₃)-propyl, 1-cyclobutyl-1-(CF₃)-methyl, 1-cyclobutyl-2-(CF₃)-ethyl, 1-cyclobutyl-3-(CF₃)-propyl, or (cyclopropyl)₂CH.

[0091] In yet further embodiments according to the first, second, and third aspects, compounds of Formula (I) include those wherein R⁴ is H.

[0092] In even further embodiments according to the first, second, and third aspects, compounds of Formula (I) include those wherein Ar is phenyl substituted with 0 to 5 R^(9a). Alternatively, Ar can be pyridyl substituted with 0 to 4 R^(9b) or pyrimidinyl substituted with 0 to 4 R^(9b).

[0093] In a fourth aspect, the present invention includes compounds of Formula (I) wherein:

[0094] A is N or CR⁴;

[0095] Ar is phenyl substituted with 0 to 3 substituents each independently selected from F, Cl, Br, CN, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, isopropoxy, CF₃, CHF₂, and OCF₃; or

[0096] Ar is pyridyl or pyrimidinyl substituted with 0 to 2 substituents each independently selected from F, Cl, Br, CN, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, isopropoxy, CF₃, CHF₂, and OCF₃;

[0097] R¹ is H, CN, OH, methyl, ethyl, methoxy, or C₁-C₂ haloalkyl;

[0098] R² is H;

[0099] R^(3e) is C₁-C₆ alkyl substituted with 0 to 2 R^(3a); and

[0100] R⁴ is H. Remaining variables can be defined as described above in the third aspect of the invention.

[0101] In embodiments according to the above first, second, third, and fourth aspects, Ar can be phenyl substituted with 0 to 3 substituents each independently selected from F, Cl, Br, CN, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, isopropoxy, CF₃, CHF₂, and OCF₃.

[0102] In further embodiments according to the above first, second, third, and fourth aspects, Ar can be pyridyl or pyrimidinyl substituted with 0 to 2 substituents each independently selected from F, Cl, Br, CN, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, isopropoxy, CF₃, CHF₂, and OCF₃. In some embodiments, pyridyl can be pyrid-3-yl.

[0103] In yet further embodiments according to the above first, second, third, and fourth aspects, A can be N or A can be CR⁴.

[0104] In even further embodiments according to the above first, second, third, and fourth aspects, R³ can be butyl, pentyl, hexyl, heptyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, methoxyhexyl, thiomethoxyethyl, thiomethoxypropyl, thiomethoxybutyl, thiomethoxypentyl, thiomethoxyhexyl, 1-cyclopropylpropyl, 1-cyclopropylbutyl, 1-cyclopropylpentyl, 1-cyclobutylpropyl, 1-cyclobutylbutyl, 1-cyclobutylpentyl, 1-cyclopropyl-1-(CF₃)-methyl, 1-cyclopropyl-1-(CF₃)-ethyl, 1-cyclopropyl-1-(CF₃)-propyl, 1-cyclobutyl-1-(CF₃)-methyl, 1-cyclobutyl-2-(CF₃)-ethyl, 1-cyclobutyl-3-(CF₃)-propyl, or (cyclopropyl)₂CH.

[0105] In a fifth aspect, the present invention includes the compounds of Formula (Ia):

[0106] selected from the group consisting of:

[0107] (R)-8-(2,4-dichloro-phenyl)-4-isobutyl-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one;

[0108] (S)-8-(2,4-dichloro-phenyl)-4-isobutyl-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one;

[0109] (R)-8-(2,4-dichloro-phenyl)-2-methyl-4-(1-methyl-butyl)-4H-pyrido[2,3-b]pyrazin-3-one;

[0110] (S)-8-(2,4-dichloro-phenyl)-2-methyl-4-(1-methyl-butyl)-4H-pyrido[2,3-b]pyrazin-3-one;

[0111] (S)-4-(1-cyclopropyl-propyl)-8-(2,4-dichloro-phenyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one;

[0112] (R)-4-(1-cyclopropyl-propyl)-8-(2,4-dichloro-phenyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one;

[0113] (R)-8-(2,4-dichloro-phenyl)-4-(1,2-dimethyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one;

[0114] (S)-8-(2,4-dichloro-phenyl)-4-(1,2-dimethyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one;

[0115] (R)-4-(1-cyclopropyl-butyl)-8-(2,4-dichloro-phenyl)-2-methyl-4H-pyrido[2,3-]pyrazin-3-one;

[0116] (S)-4-(1-cyclopropyl-butyl)-8-(2,4-dichloro-phenyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one;

[0117] (R)-8-(2,4-dichloro-phenyl)-4-(2-methoxy-1-methyl-ethyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one;

[0118] (S)-8-(2,4-dichloro-phenyl)-4-(2-methoxy-1-methyl-ethyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one;

[0119] (S)-8-(2,4-dichloro-phenyl)-4-(1-methoxymethyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one;

[0120] (R)-8-(2,4-dichloro-phenyl)-4-(1-methoxymethyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one;

[0121] (R,S)-8-(2-chloro-4-methoxy-phenyl)-2-methyl-4-(1-propyl-butyl)-4H-pyrido[2,3-b]pyrazin-3-one;

[0122] (S)-8-(2-chloro-4-methoxy-phenyl)-4-(1-cyclopropyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one;

[0123] (R)-8-(2-chloro-4-methoxy-phenyl)-4-(1-cyclopropyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one;

[0124] (R)-8-(2-chloro-4-methoxy-phenyl)-4-(1-cyclobutyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one;

[0125] (S)-8-(2-chloro-4-methoxy-phenyl)-4-(1-cyclobutyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one;

[0126] (S)-8-(2-chloro-4-methoxy-phenyl)-4-(2-methoxy-1-methyl-ethyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one;

[0127] (R)-8-(2-chloro-4-methoxy-phenyl)-4-(2-methoxy-1-methyl-ethyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one;

[0128] (S)-8-(2-chloro-4-methoxy-phenyl)-4-(1-methoxymethyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one;

[0129] (R)-4-(1-cylcopropropyl-propyl)-8-(4-methoxy-2-methyl-phenyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one;

[0130] (R)-4-(1-cyclopropyl-butyl)-8-(4-methoxy-2-methyl-phenyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one;

[0131] (S)-4-(1-cyclopropyl-butyl)-8-(4-methoxy-2-methyl-phenyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one;

[0132] (R)-4-(2-methoxy-1-methyl-ethyl)-8-(4-methoxy-2-methyl-phenyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one;

[0133] (R)-4-(1-ethyl-pentyl)-8-(6-methoxy-2-methyl-pyridin-3-yl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one;

[0134] (S)-4-(1-ethyl-pentyl)-8-(6-methoxy-2-methyl-pyridin-3-yl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one;

[0135] (R)-4-(1-cyclopropyl-propyl)-8-(6-methoxy-2-methyl-pyridin-3-yl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one;

[0136] (R)-4-(1-cyclopropyl-butyl)-8-(6-methoxy-2-methyl-pyridin-3-yl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one;

[0137] (S)-4-(1-cyclopropyl-butyl)-8-(6-methoxy-2-methyl-pyridin-3-yl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one;

[0138] (R)-4-(2-methoxy-1-methyl-ethyl)-8-(6-methoxy-2-methyl-pyridyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one;

[0139] (R)-4-sec-butyl-8-(2-chloro-4-difluoromethoxy-phenyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one;

[0140] (S)-4-(1-cyclopropyl-butyl)-8-(6-methoxy-2-methyl-pyridin-3-yl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one;

[0141] (S)-8-(2-chloro-4-difluoromethoxy-phenyl)-4-(1-cyclopropyl-propyl)2-methyl-4H-pyrido[2,3-b]pyrazin-3-one;

[0142] (R)-8-(2-chloro-4-difluoromethoxy-phenyl)-4-(1-cyclopropyl-propyl)2-methyl-4H-pyrido[2,3-b]pyrazin-3-one;

[0143] (R)-8-(2-chloro-4-difluoromethoxy-phenyl)-4-(1-cyclopropyl-butyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one;

[0144] (S)-8-(2-chloro-4-difluoromethoxy-phenyl)-4-(1-cyclopropyl-butyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one;

[0145] (R)-8-(2-chloro-4-difluoromethoxy-phenyl)-4-(2-methoxy-1-methyl-ethyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one;

[0146] (R)-8-(2-chloro-4-difluoromethoxy-phenyl)-4-(1-methoxymethyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one;

[0147] (S)-8-(2-chloro-4-difluoromethoxy-phenyl)-4-(1-methoxymethyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one;

[0148] (S)-8-(2-chloro-4-trifluoromethyl-phenyl)-4-(1-cyclopropyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one;

[0149] (R)-8-(2-chloro-4-trifluoromethyl-phenyl)-4-(2-methoxy-1-methyl-ethyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one;

[0150] (R)-8-(2-chloro-4-trifluoromethyl-phenyl)-4-(1-methoxymethyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one;

[0151] (R)-3-chloro-4-(4-(1-methoxymethylpropyl)-2-methyl-3-oxo-3,4-dihydro-pyrido[2,3-b]pyrazin-8-yl]-benzonitrile;

[0152] (R)-8-sec-butyl-4-(2,4-dichloro-phenyl)-6-methyl-8H-pteridin-7-one; and

[0153] (S)-8-sec-butyl-4-(2,4-dichloro-phenyl)-6-methyl-8H-pteridin-7-one.

[0154] In a sixth aspect of the invention, there are provided compounds of Formula (Ib):

[0155] selected from the group consisting of:

[0156] (R)-5-(2,4-Dichloro-phenyl)-1-isobutyl-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0157] (S)-5-(2,4-Dichloro-phenyl)-1-isobutyl-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0158] (R)-1-(1-Cyclopropyl-propyl)-5-(2,4-dichloro-phenyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0159] (S)-1-(1-Cyclopropyl-propyl)-5-(2,4-dichloro-phenyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0160] (R)-5-(2,4-Dichloro-phenyl)-1-(1-methoxymethyl-propyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0161] (S)-5-(2,4-Dichloro-phenyl)-1-(1-methoxymethyl-propyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0162] (R)-5-(2,4-Dichloro-phenyl)-1-(2-methoxy-1-methyl-ethyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0163] (S)-5-(2,4-Dichloro-phenyl)-1-(2-methoxy-1-methyl-ethyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0164] (R)-1-(1-Cyclopropyl-2-methoxy-ethyl)-5-(2,4-dichloro-phenyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0165] (S)-1-(1-Cyclopropyl-2-methoxy-ethyl)-5-(2,4-dichloro-phenyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0166] (R)-1-(1-Cyclobutyl-ethyl)-5-(2,4-dichloro-phenyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0167] (S)-1-(1-Cyclobutyl-ethyl)-5-(2,4-dichloro-phenyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0168] (R)-1-(1-Cyclobutyl-propyl)-5-(2,4-dichloro-phenyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0169] (S)-1-(1-Cyclobutyl-propyl)-5-(2,4-dichloro-phenyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0170] (R)-5-(2-Chloro-5-fluoro-4-methoxy-phenyl)-1-(1-cyclopropyl-ethyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0171] (S)-5-(2-Chloro-5-fluoro-4-methoxy-phenyl)-1-(1-cyclopropyl-ethyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0172] (R)-5-(2-Chloro-5-fluoro-4-methoxy-phenyl)-1-(1-cyclopropyl-propyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0173] (S)-5-(2-Chloro-5-fluoro-4-methoxy-phenyl)-1-(1-cyclopropyl-propyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0174] (R)-5-(2-Chloro-5-fluoro-4-methoxy-phenyl)-1-(2-methoxy-1-methyl-ethyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0175] (S)-5-(2-Chloro-5-fluoro-4-methoxy-phenyl)-1-(2-methoxy-1-methyl-ethyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0176] (R)-5-(2-Chloro-5-fluoro-4-methoxy-phenyl)-1-(1-methoxymethyl-propyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0177] (S)-5-(2-Chloro-5-fluoro-4-methoxy-phenyl)-1-(1-methoxymethyl-propyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0178] (R)-5-(2-Chloro-5-fluoro-4-methoxy-phenyl)-1-(1-cyclopropyl-2-methoxy-ethyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0179] (S)-5-(2-Chloro-5-fluoro-4-methoxy-phenyl)-1-(1-cyclopropyl-2-methoxy-ethyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0180] (R)-5-(2-Chloro-5-fluoro-4-methoxy-phenyl)-1-(1-cyclobutyl-ethyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0181] (S)-5-(2-Chloro-5-fluoro-4-methoxy-phenyl)-1-(1-cyclobutyl-ethyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0182] (R)-5-(2-Chloro-5-fluoro-4-methoxy-phenyl)-1-(1-cyclobutyl-propyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0183] (S)-5-(2-Chloro-5-fluoro-4-methoxy-phenyl)-1-(1-cyclobutyl-propyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0184] (R)-1-(1-Cyclopropyl-ethyl)-5-(6-methoxy-2-methyl-pyridin-3-yl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0185] (S)-1-(1-Cyclopropyl-ethyl)-5-(6-methoxy-2-methyl-pyridin-3-yl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0186] (R)-1-(1-Cyclopropyl-propyl)-5-(6-methoxy-2-methyl-pyridin-3-yl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0187] (S)-1-(1-Cyclopropyl-propyl)-5-(6-methoxy-2-methyl-pyridin-3-yl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0188] (R)-1-(2-Methoxy-1-methyl-ethyl)-5-(6-methoxy-2-methyl-pyridin-3-yl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0189] (S)-1-(2-Methoxy-1-methyl-ethyl)-5-(6-methoxy-2-methyl-pyridin-3-yl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0190] (R)-1-(1-Methoxymethyl-propyl)-5-(6-methoxy-2-methyl-pyridin-3-yl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0191] (S)-1-(1-Methoxymethyl-propyl)-5-(6-methoxy-2-methyl-pyridin-3-yl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0192] (R)-1-(1-Cyclopropyl-2-methoxy-ethyl)-5-(6-methoxy-2-methyl-pyridin-3-yl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0193] (S)-1-(1-Cyclopropyl-2-methoxy-ethyl)-5-(6-methoxy-2-methyl-pyridin-3-yl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0194] (R)-1-(1-Cyclobutyl-ethyl)-5-(6-methoxy-2-methyl-pyridin-3-yl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0195] (S)-1-(1-Cyclobutyl-ethyl)-5-(6-methoxy-2-methyl-pyridin-3-yl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0196] (R)-1-(1-Cyclobutyl-propyl)-5-(6-methoxy-2-methyl-pyridin-3-yl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0197] (S)-1-(1-Cyclobutyl-propyl)-5-(6-methoxy-2-methyl-pyridin-3-yl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0198] (R)-1-(1-Cyclopropyl-ethyl)-5-(6-methoxy-2,5-dimethyl-pyridin-3-yl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0199] (S)-1-(1-Cyclopropyl-ethyl)-5-(6-methoxy-2,5-dimethyl-pyridin-3-yl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0200] (R)-1-(1-Cyclopropyl-propyl)-5-(6-methoxy-2,5-dimethyl-pyridin-3-yl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0201] (S)-1-(1-Cyclopropyl-propyl)-5-(6-methoxy-2,5-dimethyl-pyridin-3-yl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0202] (R)-5-(6-Methoxy-2,5-dimethyl-pyridin-3-yl)-1-(2-methoxy-1-methyl-ethyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0203] (S)-5-(6-Methoxy-2,5-dimethyl-pyridin-3-yl)-1-(2-methoxy-1-methyl-ethyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0204] (R)-5-(6-Methoxy-2,5-dimethyl-pyridin-3-yl)-1-(1-methoxymethyl-propyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0205] (S)-5-(6-Methoxy-2,5-dimethyl-pyridin-3-yl)-1-(1-methoxymethyl-propyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0206] (R)-1-(-Cyclopropyl-2-methoxy-ethyl)-5-(6-methoxy-2,5-dimethyl-pyridin-3-yl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0207] (S)-1-(1-Cyclopropyl-2-methoxy-ethyl)-5-(6-methoxy-2,5-dimethyl-pyridin-3-yl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0208] (R)-1-(1-Cyclobutyl-ethyl)-5-(6-methoxy-2,5-dimethyl-pyridin-3-yl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0209] (S)-1-(1-Cyclobutyl-ethyl)-5-(6-methoxy-2,5-dimethyl-pyridin-3-yl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0210] (R)-1-(1-Cyclobutyl-propyl)-5-(6-methoxy-2,5-dimethyl-pyridin-3-yl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0211] (S)-1-(1-Cyclobutyl-propyl)-5-(6-methoxy-2,5-dimethyl-pyridin-3-yl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0212] (R)-1-(1-Cyclopropyl-ethyl)-5-(4-methoxy-2,5-dimethyl-phenyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0213] (S)-1-(1-Cyclopropyl-ethyl)-5-(4-methoxy-2,5-dimethyl-phenyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0214] (R)-1-(1-Cyclopropyl-propyl)-5-(4-methoxy-2,5-dimethyl-phenyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0215] (S)-1-(1-Cyclopropyl-propyl)-5-(4-methoxy-2,5-dimethyl-phenyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0216] (R)-5-(4-Methoxy-2,5-dimethyl-phenyl)-1-(2-methoxy-1-methyl-ethyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0217] (S)-5-(4-Methoxy-2,5-dimethyl-phenyl)-1-(2-methoxy-1-methyl-ethyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0218] (R)-5-(4-Methoxy-2,5-dimethyl-phenyl)-1-(1-methoxymethyl-propyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0219] (S)-5-(4-Methoxy-2,5-dimethyl-phenyl)-1-(1-methoxymethyl-propyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0220] (R)-1-(1-Cyclopropyl-2-methoxy-ethyl)-5-(4-methoxy-2,5-dimethyl-phenyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0221] (S)-1-(1-Cyclopropyl-2-methoxy-ethyl)-5-(4-methoxy-2,5-dimethyl-phenyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0222] (R)-1-(1-Cyclobutyl-ethyl)-5-(4-methoxy-2,5-dimethyl-phenyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0223] (S)-1-(1-Cyclobutyl-ethyl)-5-(4-methoxy-2,5-dimethyl-phenyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0224] (R)-1-(1-Cyclobutyl-propyl)-5-(4-methoxy-2,5-dimethyl-phenyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0225] (S)-1-(1-Cyclobutyl-propyl)-5-(4-methoxy-2,5-dimethyl-phenyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0226] (R)-1-(1-Cyclopropyl-ethyl)-5-(2,4-dimethoxy-pyrimidin-5-yl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0227] (S)-1-(1-Cyclopropyl-ethyl)-5-(2,4-dimethoxy-pyrimidin-5-yl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0228] (R)-1-(1-Cyclopropyl-propyl)-5-(2,4-dimethoxy-pyrimidin-5-yl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0229] (S)-1-(1-Cyclopropyl-propyl)-5-(2,4-dimethoxy-pyrimidin-5-yl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0230] (R)-5-(2,4-Dimethoxy-pyrimidin-5-yl)-1-(2-methoxy-1-methyl-ethyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0231] (S)-5-(2,4-Dimethoxy-pyrimidin-5-yl)-1-(2-methoxy-1-methyl-ethyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0232] (R)-5-(2,4-Dimethoxy-pyrimidin-5-yl)-1-(1-methoxymethyl-propyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0233] (S)-5-(2,4-Dimethoxy-pyrimidin-5-yl)-1-(1-methoxymethyl-propyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0234] (R)-1-(1-Cyclopropyl-2-methoxy-ethyl)-5-(2,4-dimethoxy-pyrimidin-5-yl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0235] (S)-1-(1-Cyclopropyl-2-methoxy-ethyl)-5-(2,4-dimethoxy-pyrimidin-5-yl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0236] (R)-1-(1-Cyclobutyl-ethyl)-5-(2,4-dimethoxy-pyrimidin-5-yl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0237] (S)-1-(1-Cyclobutyl-ethyl)-5-(2,4-dimethoxy-pyrimidin-5-yl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0238] (R)-1-(1-Cyclobutyl-propyl)-5-(2,4-dimethoxy-pyrimidin-5-yl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one;

[0239] (S)-1-(1-Cyclobutyl-propyl)-5-(2,4-dimethoxy-pyrimidin-5-yl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one.

[0240] Compounds of this invention can have one or more asymmetric centers. Unless otherwise indicated, all chiral (enantiomeric and diastereomeric) and racemic forms of compounds of Formula (I) are included in the present invention. Many geometric isomers of olefins, C═N double bonds, and the like can also be present in the compounds, and all such stable isomers are contemplated in the present invention. Accordingly, the present compounds can be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. All chiral, (enantiomeric and diastereomeric) and racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomer form is specifically indicated.

[0241] The term “alkyl” as used herein is meant to refer to a saturated hydrocarbon group which is straight-chained, branched or cyclized (“cycloalkyl”). Alkyl groups can be unsubstituted or substituted so that one or more of its hydrogens are replaced by another chemical group. Example alkyl groups include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), cyclopentyl, cyclohexyl, norbornyl, and the like. “Alkenyl” refers to alkyl groups having one or more double carbon-carbon bonds. Example alkenyl groups include ethenyl, propenyl, cyclohexenyl, and the like. “Alkynyl” refers to alkyl groups having one or more triple carbon-carbon bonds. Example alkynyl groups include ethynyl, propynyl, and the like. “Haloalkyl” refers to branched, straight-chained, and cyclyl alkyl groups having one or more halogen substituents. Example haloalkyl groups include CF₃, C₂F₅, CHF₂, CCl₃, CHCl₂, C₂Cl₅, and the like. The term “alkoxy” refers to an —O-alkyl group. Example alkoxy groups include, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like. The term “cycloalkyl” refers to cyclized alkyl groups, including mono-, bi- or poly-cyclic ring systems. Example cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and so forth. “Halo” or “halogen” includes fluoro, chloro, bromo, and iodo.

[0242] “Aryl” groups refer to monocyclic or polycyclic aromatic hydrocarbons, including, for example, phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, and the like. Aryl moieties are well known and described, for example, in Hawley's Condensed Chemical Dictionary (13 ed.), R. J. Lewis, ed., J. Wiley & Sons, Inc., New York (1997). Aryl groups can be substituted or unsubstituted.

[0243] “Heteroaryl” groups are monocyclic and polycyclic aromatic hydrocarbons that include at least one heteroatom ring member such as sulfur, oxygen, or nitrogen. Heteroaryl groups include, without limitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide, benzoxazolin-2-on-yl, indolinyl, benzodioxolanyl, benzodioxane, and the like. Heteroaryl groups can be substituted or unsubstituted.

[0244] “Heterocyclyl” groups can be saturated (i.e., containing no double or triple bonds) or unsaturated (i.e., containing one or more double or triple bonds) carbocyclyl groups wherein one or more of the ring-forming carbon atoms of the carbocyclyl group is replaced by a heteroatom such as O, S, or N. Heterocyclyl groups can be substituted or unsubstituted. Examples of heterocyclyl groups include morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, and the like. Some example heterocyclyl substituents can include C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halogen, C₁-C₄ haloalkyl, CN, OR⁷, SH, NO₂, OCF₃, S(O)_(n)R⁷, COR⁷, CO₂R⁷, OC(O)R⁷, NR⁷COR⁸, N(COR⁷)₂, NR⁷CONR⁷R⁸, NR⁷CO₂R⁸, NR⁷R⁸, or CONR⁷R⁸, wherein R⁷ and R⁸ are as defined above according to the first aspect of the invention. Heterocyclyl groups can be substituted with any number of substituents such as, for example, 0 to 7, 0 to 6, 0 to 5, 0 to 4, 0 to 3, 0 to 2, or 0 to 1 substituents.

[0245] As referred to herein, the term “substituted” means that one or more hydrogen atoms is replaced with a non-hydrogen group, provided that normal valencies are maintained and that the substitution results in a stable compound.

[0246] The term “pharmaceutically acceptable salt” refers to acid or base salts of the compounds described herein. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. Pharmaceutically acceptable salts of the compounds of the invention can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference in its entirety. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. Pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. Such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.

[0247] “Prodrugs” refer to inactive compounds that can be converted upon absorption by a mammalian subject to an active compound of Formula (I). Prodrugs of the compounds of Formula (I) can be prepared by modifying functional groups present in the compounds of Formula (I) in such a way that the modifications are cleaved in vivo to produce the parent compounds. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of Formula (I). Preparation of prodrugs is well known in the art and described in, for example, Medicinal Chemistry: Principles and Practice, ed. F. D. King, The Royal Society of Chemistry, Cambridge, UK, 1994, which is incorporated herein by reference in its entirety.

[0248] Radiolabelled compounds of Formula I, i.e., wherein one or more of the atoms described are replaced by a radioactive isotope of that atom (e.g., C replaced by ¹⁴C or by ¹¹C, and H replaced by ³H or ¹⁸F), are also provided herein. Such compounds have a variety of potential uses, e.g., as standards and reagents in determining the ability of a potential pharmaceutical to bind to target proteins or receptors, or for imaging compounds of this invention bound to biological receptors in vivo or in vitro.

[0249] The present invention further includes compositions comprising one or more compounds of Formula (I) and a pharmaceutically acceptable carrier.

[0250] A “pharmaceutically acceptable carrier” refers to media generally accepted in the art for the delivery of biologically active agents to animals, in particular, mammals. Pharmaceutically acceptable carriers are formulated according to a number of factors well within the purview of those of ordinary skill in the art. These include, without limitation: the type and nature of the active agent being formulated; the subject to which the agent-containing composition is to be administered; the intended route of administration of the composition; and, the therapeutic indication being targeted. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as a variety of solid and semi-solid dosage forms. Such carriers can include a number of different ingredients and additives in addition to the active agent, such additional ingredients being included in the formulation for a variety of reasons, e.g., stabilization of the active agent, binders, etc., well known to those of ordinary skill in the art. Descriptions of suitable pharmaceutically acceptable carriers, and factors involved in their selection, are found in a variety of readily available sources such as, for example, Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, which is incorporated herein by reference in its entirety.

[0251] The present invention further includes methods of reducing symptoms caused by elevated levels of corticotropin releasing factor in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of Formula (I).

[0252] The present invention further includes methods of treating stress-related symptoms in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of Formula (I).

[0253] The present invention also includes methods of treating a disorder characterized by abnormal levels of corticotropin releasing factor in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of Formula (I). According to some embodiments, the disorder can be characterized by elevated levels of corticotropin releasing factor. In some embodiments, the disorder affects the central nervous system. Some example disorders that can be treated according to the methods described herein include anxiety or depression. In some embodiments, the treatable disorder is irritable bowel syndrome.

[0254] Some disorders characterized by abnormal levels of corticotropin releasing factor include the following disorders: mood disorders such as depression, including major depression, single episode depression, recurrent depression, child abuse induced depression, seasonal affective disorder, postpartum depression, dysthemia, bipolar disorders, and cyclothymia; anxiety disorders including panic, phobias, obsessive-compulsive disorder; post-traumatic stress disorder; and sleep disorders induced by stress; inflammation; pain; chronic fatigue syndrome; stress-induced headache; cancer; human immunodeficiency virus (HIV) infections; neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and Huntington's disease; gastrointestinal diseases such as ulcers, irritable bowel syndrome, Crohn's disease, spastic colon, diarrhea, and post operative ileus, and colonic hypersensitivity associated by psychopathological disturbances or stress; eating disorders such as anorexia and bulimia nervosa; supranuclear palsy; amyotrophic lateral sclerosis; immune suppression; hemorrhagic stress; stress-induced psychotic episodes; euthyroid sick syndrome; syndrome of inappropriate antidiarrhetic hormone (ADH); obesity; infertility; head traumas; spinal cord trauma; ischemic neuronal damage (e.g., cerebral ischemia such as cerebral hippocampal ischemia); excitotoxic neuronal damage; epilepsy; cardiovascular disorders including hypertension, tachycardia and congestive heart failure; stroke; immune dysfunctions including stress-induced immune dysfunctions (e.g., stress induced fevers, porcine stress syndrome, bovine shipping fever, equine paroxysmal fibrillation, and dysfunctions induced by confinement in chickens, sheering stress in sheep or human-animal interaction related stress in dogs); muscular spasms; urinary incontinence; senile dementia of the Alzheimer's type; multiinfarct dementia; amyotrophic lateral sclerosis; chemical dependencies and addictions (e.g., dependencies on alcohol, cocaine, heroin, benzodiazepines, or other drugs); drug and alcohol withdrawal symptoms; osteoporosis; psychosocial dwarfism; hypoglycemia; hair loss; abnormal circadian rhythm; and disorders related to abnormal circadian rhythm such as time zone change syndrome, seasonal affective disorder, irregular sleep-wake pattern, delayed sleep phase syndrome, advanced sleep phase syndrome, non-24 hour sleep wake disorder, light-induced clock resetting, REM sleep disorder, hypersomnia, parasomnia, narcolepsy, nocturnal enuresis, restless legs syndrome, sleep apnea, dysthymia, and abnormal circadian rhythm associated with chronic administration and withdrawal of antidepressant agents. Thus, the compounds provided herein, because of their antagonism of CRF receptors, are expected to be useful in treating these and other disorders.

[0255] The term “therapeutically effective amount” refers to an amount of compound effective to reduce or eliminate at least one symptom of a disorder that the compound was used to treat.

[0256] Compounds of this invention can be administered to treat the above disorders by any suitable means that allows the compound to contact the compound's site of action, such as a CRF receptor, in the body of a mammal. The compounds can be administered by any conventional means available for use in conjunction with pharmaceuticals either as an individual therapeutic agent or in combination with other therapeutic agents. Compounds of the present invention can be administered alone, or in combination with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

[0257] The dosage of compound administered varies depending on several factors such as the pharmacodynamic character of the particular compound, and its mode and route of administration; the recipient's age, weight, and health; nature and extent of symptoms; kind of concurrent treatment; frequency of treatment; and desired effect. For use in the treatment of the above diseases or conditions, the compounds of this invention can be orally administered daily at a dosage of the active ingredient (e.g., a compound of Formula I) of about 0.002 to about 200 mg/kg of body weight. For example, a dose of about 0.01 to about 10 mg/kg can be divided into smaller doses and administered one to four times a day. Alternatively, sustained release formulations can be effective in obtaining the desired pharmacological effect.

[0258] Dosage forms (compositions) suitable for administration can contain from about 1 mg to about 100 mg of active ingredient per dosage unit. In these pharmaceutical compositions, the active ingredient (e.g., a compound of Formula I) can be present in an amount of about 0.5 to 95% by weight based on the total weight of the composition.

[0259] The active ingredient (e.g., a compound of Formula I) can be administered orally in solid dosage forms such as capsules, tablets and powders, or in liquid forms such as elixirs, syrups, and/or suspensions. The compounds of this invention can also be administered parenterally in sterile liquid dose formulations.

[0260] Gelatin capsules can be used to contain the active ingredient and a suitable carrier such as, but not limited to, lactose, starch, magnesium stearate, steric acid, or cellulose derivatives. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of time. Compressed tablets can be sugar-coated or film-coated to mask any unpleasant taste, or used to protect the active ingredients from the atmosphere, or to allow selective disintegration of the tablet in the gastrointestinal tract.

[0261] Liquid dose forms for oral administration can also contain coloring or flavoring agents to increase patient acceptance.

[0262] Typically, water, pharmaceutically acceptable oils, saline, aqueous dextrose, and related sugar solutions and glycols, such as propylene glycol or polyethylene glycol, are suitable carriers for parenteral solutions. Solutions for parenteral administration can contain, for example, a water soluble salt of the active ingredient and suitable stabilizing agents. Antioxidizing agents, such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or in combination, can act as suitable stabilizing agents. Also suitable as stabilizing agents are citric acid and its salts, and EDTA. In addition, parenteral solutions can contain preservatives such as, for example, benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.

[0263] The compounds of this invention may also be used as reagents or standards in the biochemical study of neurological function, dysfunction, and disease.

[0264] Compounds of Formula (I) can be prepared by the following synthetic routes and schemes. Where a detailed description is not provided, it is assumed that those skilled in the art of organic synthesis will readily understand the meaning.

[0265] Compounds of Formula (I) can be prepared according to the route shown in Scheme 1.

[0266] According to scheme 1, a compound of Formula II can be coupled to an aromatic compound of Formula III, with elimination of M—K. For compounds of Formula II, K can represent a halide, pseudohalide (such as, for example, mesylate, tosylate or triflate), or thiomethyl. For compounds of Formula III, M can represent groups such as lithium, bromomagnesium, chlorozinc, (dihydroxy)boron, (dialkoxy)boron, trialkylstannyl, and the like. The coupling reaction of scheme 1 can be performed in the presence of an appropriate catalyst, such as tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,3-bis(diphenylphosphino)propane]nickel dichloride, etc. Example methods involve the coupling of chloroheterocycles with in-situ-prepared arylzinc reagents according to the method described in Negishi et al., J. Org. Chem. 1977, 42, 1821, which is incorporated herein by reference in its entirety, and the coupling with arylboronic esters according to the method described in Suzuki et al., Chem. Letters 1989, 1405, which is incorporated herein by reference in its entirety. Appropriate solvents for reactions of this type usually include, for example, tetrahydrofuran, diethyl ether, dimethylformamide, or dimethylsulfoxide. Typical temperatures can range, for example, from ambient up to the boiling point of the solvent.

[0267] Preparation of compounds of Formula VI wherein A is a nitrogen atom can proceed according to the route of Scheme 2.

[0268] A compound of Formula IV, such as, for example, when K is chloride, can be obtained from commercial sources. Compounds bearing pseudohalide K groups can be made from the corresponding dihydroxy compounds by treatment with an appropriate activating reagent, such as an organosulfonic anhydride or sulfonyl chloride. Compounds of Formula IV can be converted to compounds of Formula VI by, for example, (i) monoalkylation with a compound P—NH₂, followed by reduction of the nitro group, or (ii) reduction of the nitro group, to give an amine compound of Formula V, followed by monoalkylation with a compound R³—NH₂. Pyrimidine chemistry of this type is well represented in the literature, and is reviewed in Comprehensive Heterocyclic Chemistry, vol. 6, which is incorporated herein by reference in its entirety. Alkylation of chloropyrimidines with amine compounds can be accomplished under either acidic (e.g., HCl or acetic) or basic (e.g., trialkylamines, potassium tert-butoxide, etc.) conditions. Nitro groups in compounds of this type can be reduced to amino groups using one of any number of conditions, including catalytic hydrogenation, tin dichloride, sodium dithionite, zinc metal, iron powder, etc.

[0269] Compounds of Formula VI can be cyclized with an appropriate ketoester by condensation followed by intramolecular cyclization in toluene, ethanol, methanol, butanol, or other appropriate solvent either alone or in the presence of acid such as a toluenesulfonic acid, acetic acid, hydrochloric acid, Lewis acid, etc. The reaction can be run at any suitable temperature such as, for example, ambient temperature to the boiling point of any given solvent to give the compounds of Formula (I).

[0270] An example preparation of compounds of Formula V, wherein A is carbon and B is nitrogen, is shown in Scheme 3.

[0271] An hydroxypyridone compound of Formula VII can be nitrated to give compounds of Formula VIII employing conditions such as, for example, concentrated or fuming nitric acid, optionally in the presence of concentrated sulfuric or acetic acid. Both the hydroxy and pyridone groups in compounds of Formula VIII can be activated at the same time, using stronger conditions such as phosphorus oxychloride and heat, or excess toluenesulfonic anhydride, to give compounds of Formula IX. Selective monoalkylation of compounds of Formula IX is also possible, but can give mixtures of regioisomeric products. The nitro group of compounds of Formula X can then be reduced as discussed above, to give compounds of Formula V wherein A is CR⁴. Cyclization as described above can yield compounds of Formula (I).

[0272] Another route (scheme 4) can convert compounds of Formula II to the metallated compounds of Formula XI for coupling to appropriate aryl halides as described above.

[0273] The compound of Formula II (A═N) can also be synthesized by direct halogenation of compounds of Formula XII (scheme 5). This can be achieved selectively by forming the N-oxide with meta-chloroperbenzoic acid, or other appropriate oxidizing agents followed by treatment with a halogenating agent such as phosphorous oxychloride as described in Tomczuk et al., J. Med. Chem., 1991, 34, 2993, which is incorporated herein by reference in its entirety.

[0274] Compounds of Formula V, which are typically commercially available, can be exposed to aryl coupling conditions (scheme 6) as described above to give compounds of Formula XIII, which can be elaborated to give compounds of Formula XIV, which upon treatment with an appropriate keto-ester under conditions described can give rise to compounds of Formula (I) where A═N.

[0275] Compounds of Formula XV (scheme 7), which are typically commercially available, can be reacted with an appropriate amine to give compounds of Formula XVI. The nitro group can then be reduced as described above and compounds of Formula XVIII cyclized with the desired ketoester in a manner analogous to the cyclizations previously described. This cyclized material can then be halogenated to give the desired halide derivative which, in turn, can be subjected to aryl coupling conditions as previously described to give the desired analogs. Alternatively, compounds of Formula XVIII can be directly metallated and the organolithium subjected to aryl coupling conditions as described above. Compounds of Formula XVIII can also be used as a precursor to XIX following reaction conditions described earlier.

[0276] Commercially available compounds of Formula VII can be nitrated employing conditions such as fuming nitric acid, optionally in the presence of concentrated sulfuric or acetic acid (scheme 8). The hydroxypyridone compounds of Formula VIII can be selectively protected. One method of protection, for example, involves the treatment of dicyclohexylamine salts of compounds of Formula VIII. Conversion of compounds of Formula XXI, where K=Cl, can be achieved by treatment with sulfonyl chloride, or if K is a pseudohalide, treatment with organicsulfonic anhydride. The coupling reaction can be run as described above to give compounds of Formula XXII and the nitro group reduced using catalytic hydrogenation, tin dichloride, sodiumithionite, etc. Cyclization as described above can give compounds of Formula I, where A=CR⁴.

[0277] Methods of synthesis of compounds R³—OH, R³—J and R³—NH₂ are related, in that the alcohol can be used in the synthesis of the other two compounds, as is shown in Scheme 9.

[0278] For example, the hydroxy group can be converted to the following J groups, using the indicated reagents (this route is not limited to these J groups): methanesulfonate, using methanesulfonyl chloride or anhydride and an appropriate base; toluenesulfonate, using toluenesulfonyl chloride or anhydride and an appropriate base; iodide; using iodine/triphenylphosphine; bromide, using phosphorus tribromide or carbon tetrabromide/triphenylphosphine; or trifluoromethanesulfonate, using trifluoromethane-sulfonic anhydride and an appropriate base. Both compounds R³—OH and R³—J are used in the methods portrayed in Scheme 1. Conversion of R³—J to R³—N₃ typically uses an azide source, such as sodium azide, and a solvent such as dimethylsulfoxide or dimethylformamide, or water and a phase-transfer catalyst (such as tetrabutylammonium hydrogen sulfate). Reduction of the azide compound R³—N₃ to R³—NH₂ can be accomplished using reagents such as, for example, sodium borohydride or triphenylphosphine, or hydrogen gas and a catalyst (such as palladium on carbon). The amine R³—NH₂ can then be employed in the methods portrayed in Scheme 2.

[0279] In the cases where the compound R³—OH could be represented by Formula XXIV (Scheme 10), wherein R^(a) and R^(b) represent substructures which, taken together with the carbinol methine group, comprise the entire group R³, this compound can be prepared by addition to a carbonyl compound.

[0280] This route can be useful in the case where R^(a) or R^(b) represent a cycloalkyl group, such as cyclopropyl. An organometallic reagent (where M′ represents a metallic group, such as Li, CuCN, CuI, MgCl, MgBr, MgI, ZnCl, CrCl, etc.) can be allowed to react with an aldehyde reagent to prepare the alcohol compound of Formula XXIV. Alternatively, a ketone of Formula XXV can be treated with a reducing agent, such as, for example, sodium borohydride, lithium aluminum hydride, etc., which can also generate the alcohol of Formula XXIV. Standard methods of ketone synthesis can be used where appropriate in the preparation of compounds of Formula XXV, which are familiar to those skilled in the art of organic synthesis.

[0281] An homologous approach can also be employed in the synthesis of alcohols R³—OH, involving the ring-opening reaction of cyclic ether compounds with organometallic reagents (Scheme 11).

[0282] Here, an organometallic reagent R^(a)—M″ is used, where M″ represents metals such as Mg, Zn or Cu. An example method is described in Huynh, et al., Tetrahedron Letters 1979, 17, 1503-1506, which is incorporated herein by reference in its entirety, where organomagnesium reagents are reacted with cyclic ethers with catalysis provided by copper (I) iodide. Use of an epoxide compound of Formula XXVII in this manner can result in synthesis of an alcohol compound of Formula XXVIII, and use of an oxetane compound of Formula XXVI can generate an alcohol of Formula XXIX. Both compounds XXVIII and XXIX are variants of R³—OH.

[0283] Synthesis of compound R³—NH₂ with Formula XXX is portrayed in Scheme 12.

[0284] A simple reductive amination of ketones of Formula XXV can produce amines of Formula XXX. This reaction can be performed using anhydrous ammonia in the presence of hydrogen and a catalyst. Alternatively, addition of an organometallic reagent to a nitrile compound gives an imine, which can be treated in situ with a reducing agent (such as, for example, sodium cyanoborohydride) to give amines of Formula XXX. Further, a compound of Formula XXXII, wherein Q is an optionally-substituted oxygen atom (i.e., an oxime) or nitrogen atom (i.e., a hydrazone), can be allowed to react with an organometallic reagent R^(b)—M′″. Here, metallic groups M′″ such as MgBr, CuCl or CeCl₂ can be used in additions to oximes or hydrazones. The intermediate addition products of Formula XXXI can be subjected to reductive cleavage (using conditions such as sodium/liquid ammonia or catalytic hydrogenation), which can afford amines of Formula XXX.

[0285] Amino acids, either naturally-occurring or synthetic, are potential sources of useful starting materials for the synthesis of the compounds of this invention. Scheme 13 shows some possible applications of this approach.

[0286] Protected amino acids of Formula XXXIV can be prepared from the parent compounds of Formula XXXIII. Some example protecting groups (“Prot”) include tert-butoxycarbonyl, benzyloxycarbonyl, and triphenylmethyl. Standard texts in peptide chemistry describe amino protecting groups. The carboxylic acid group can be reduced using reagents such as lithium borohydride, giving, for example, alcohols of Formula XXV. The hydroxy group can be converted to a leaving group “J” as described before. The compounds of Formula XXXVI can be treated with appropriate reagents to produce a wide variety of functional groups (e.g., compounds of Formula XXXVII). For example, displacement of J with cyanide (e.g., sodium cyanide in warm dimethylformamide) can give a nitrile. Displacement of J with a mercaptan (in the presence of a base, such as potassium carbonate) can give a disulfide. Further, displacement of J with a secondary amine can give a tertiary amine, etc.

[0287] The compounds of Formula (I) with unsaturated R¹ groups can be a further source of compounds. Unsaturated (double and triple) bonds can take part in cycloaddition chemistry using appropriate reagents (Scheme 14). Cycloaddition of an alkyne compound of Formula XXXIX with 1,3-dienes to give six-membered ring compounds like that of Formula XL (commonly known as the Diels-Alder reaction), and cycloaddition with 3-atom dipolar reagents to give heterocyclic compounds of Formula XLI, are familiar to those skilled in the art of organic synthesis. An example of this approach is the synthesis of an isoxazole compound of Formula XLII from the alkyne XXXIX and a nitrile oxide reagent.

[0288] The synthetic procedure in Scheme 15 shown below can be used to prepare compounds of Formula (Ia).

[0289] Reaction of 4-chloropyridone of Formula XLIII with an aryl halide, such as benzyl bromide in benzene and in the presence of Ag₂CO₃ as described in Scheme 15 (Smith A. M. et al., J. Med. Chem., 1993, 36, 8, which is incorporated herein by reference) and at temperature ranges of, for example, about 30 to about 80° C. can afford the corresponding 2-benzyloxypyridine of Formula XLIV. This compound can be coupled, for example, with an arylboronic acid, ArB(OH)₂, under palladium-catalyzed conditions to give compounds of Formula XLV. The benzyloxy group can be removed by treatment with a strong acid, such as trifluoroacetic acid, triflic acid, sulfuric acid, HCl, etc. to give pyridones of Formula XLVI. This compound can be converted to the 2-halopyridine derivative with the action of POX₃, PX₅, (X is halo) or the corresponding triflate, tosylate or mesylate, which can be displaced with a primary amine R³NH₂ to give XLVII. The nitro group can be reduced under conditions decribed in scheme 15, and the aminopyridine can be cyclized to XLVIII under the conditions described in scheme 15.

[0290] The following examples are provided to describe the invention in further detail and are intended to illustrate and not to limit the invention. Potency of binding to CFR₁ recetor for select compounds are listed as IC₅₀ ranges where a=<1 nM; b=1-10 nM; c=10-100 nM; d=100 nM-1 μM; e=>1 μM.

EXAMPLES

[0291] TABLE 1

MS IC₅₀ Ex. R¹ R³ R^(A) R^(B) R^(C) Y Z (m/z) Range* 1 Me CH₂iPr Cl Cl H CH CH 362.3 e 2 Me CH(Me)Pr Cl Cl H CH CH 376.3 c 3 Me CH(cPr)Et Cl Cl H CH CH 388.3 b 4 Me CH(cPr)Me Cl Cl H CH CH 376.3 5 Me CH(cPr)Pr Cl Cl H CH CH 402.3 b 6 Me CH(cBu)Me Cl Cl H CH CH 7 Me CH(cBu)Et Cl Cl H CH CH 8 Me CH(cBu)Pr Cl Cl H CH CH 9 Me CH(Me)CH₂OMe Cl Cl H CH CH 378.3 c 10 Me CH(Et)CH₂OMe Cl Cl H CH CH 392.3 b 11 Me CH(CPr)CH₂OMe Cl Cl H CH CH 12 Me CH(cBu)CH₂OMe Cl Cl H CH CH 13 Me CH(nPr)CH₂OMe Cl Cl H CH CH 14 Me CH(cPr)Chd 2H₄OMe Cl Cl H CH CH 15 Me CH(cBu)Chd 2H₄OMe Cl Cl H CH CH 16 Me CH(Et)Chd 2H₄OMe Cl Cl H CH CH 17 Me CHEt₂ Cl OMe H CH CH 18 Me CHPr2 Cl OMe H CH CH 399.9 b 19 Me CH(cPr)Et Cl OMe H CH CH 383.9 a 20 Me CH(cPr)Me Cl OMe H CH CH 21 Me CH(cPr)Pr Cl OMe H CH CH 22 Me CH(cBu)Me Cl OMe H CH CH 23 Me CH(cBu)Et Cl OMe H CH CH 397.9 b 24 Me CH(cBu)Pr Cl OMe H CH CH 25 Me CH(Me)CH₂OMe Cl OMe H CH CH 373.8 c 26 Me CH(Et)CH₂OMe Cl OMe H CH CH 387.9 c 27 Me CH(cPr)CH₂OMe Cl OMe H CH CH 28 Me CH(cBu)CH₂OMe Cl OMe H CH CH 29 Me CH(nPr)CH₂OMe Cl OMe H CH CH 30 Me CH(CPr)C₂H₄OMe Cl OMe H CH CH 31 Me CH(cBu)C₂H₄OMe Cl OMe H CH CH 32 Me CH(Et)Chd 2H₄OMe Cl OMe H CH CH 33 Me CHEt2 Cl OMe H CF CH 34 Me CHPr2 Cl OMe H CF CH 35 Me CH(cPr)Et Cl OMe H CF CH 36 Me CH(cPr)Me Cl OMe H CF CH 37 Me CH(cPr)Pr Cl OMe H CF CH 38 Me CH(cBu)Me Cl OMe H CF CH 39 Me CH(cBu)Et Cl OMe H CF CH 40 Me CH(cBu)Pr Cl OMe H CF CH 41 Me CH(Me)CH₂OMe Cl OMe H CF CH 42 Me CH(Et)CH₂OMe Cl OMe H CF CH 43 Me CH(cPr)CH₂OMe Cl OMe H CF CH 44 Me CH(cBu)CH₂OMe Cl OMe H CF CH 45 Me CH(nPr)CH₂OMe Cl OMe H CF CH 46 Me CH(cPr)C₂H₄OMe Cl OMe H CF CH 47 Me CH(cBu)C₂H₄OMe Cl OMe H CF CH 48 Me CH(Et)C₂H₄OMe Cl OMe H CF CH 49 Me CHEt2 Cl Me H CH CH 50 Me CHPr2 Cl Me H CH CH 51 Me CH(cPr)Et Cl Me H CH CH 52 Me CH(cPr)Me Cl Me H CH CH 53 Me CH(cPr)Pr Cl Me H CH CH 54 Me CH(cBu)Me Cl Me H CH CH 55 Me CH(cBu)Et Cl Me H CH CH 56 Me CH(cBu)Pr Cl Me H CH CH 57 Me CH(Me)CH₂OMe Cl Me H CH CH 58 Me CH(Et)CH₂OMe Cl Me H CH CH 59 Me CH(CPr)CH₂OMe Cl Me H CH CH 60 Me CH(cBu)CH₂OMe Cl Me H CH CH 61 Me CH(nPr)CH₂OMe Cl Me H CH CH 62 Me CH(cPr)C₂H₄OMe Cl Me H CH CH 63 Me CH(cBu)C₂H₄OMe Cl Me H CH CH 64 Me CH(Et)C₂H₄OMe Cl Me H CH CH 65 Me CHEt2 Me OMe H CH CH 66 Me CH(cPr)2 Me OMe H CH CH 376.2 b 67 Me CH(cPr)Et Me OMe H CH CH 364.1 c 68 Me CH(cPr)Me Me OMe H CH CH 69 Me CH(cPr)Pr Me OMe H CH CH 378.1 b 70 Me CH(cBu)Me Me OMe H CH CH 71 Me CH(cBu)Et Me OMe H CH CH 378.2 c 72 Me CH(cBu)Pr Me OMe H CH CH 73 Me CH(Me)CH₂OMe Me OMe H CH CH 354.2 d 74 Me CH(Et)CH₂OMe Me OMe H CH CH 3683 c 75 Me CH(cPr)CH₂OMe Me OMe H CH CH 76 Me CH(cBu)CH₂OMe Me OMe H CH CH 77 Me CH(nPr)CH₂OMe Me OMe H CH CH 78 Me CH(cPr)C₂H₄OMe Me OMe H CH CH 79 Me CH(cBu)C₂H₄OMe Me OMe H CH CH 80 Me CH(Et)C₂H₄OMe Me OMe H CH CH 81 Me CHEt2 Me OMe H CF CH 82 Me CHPr2 Me OMe H CF CH 83 Me CH(cPr)Et Me OMe H CF CH 382.3 b 84 Me CH(cPr)Me Me OMe H CF CH 85 Me CH(cPr)Pr Me OMe H CF CH 86 Me CH(cBu)Me Me OMe H CF CH 87 Me CH(cBu)Et Me OMe H CF CH 88 Me CH(cBu)Pr Me OMe H CF CH 89 Me CH(Me)CH₂OMe Me OMe H CF CH 386.3 c 90 Me CH(Et)CH₂OMe Me OMe H CF CH 386.3 b 91 Me CH(cPr)CH₂OMe Me OMe H CF CH 92 Me CH(cBu)CH₂OMe Me OMe H CF CH 93 Me CH(nPr)CH₂OMe Me OMe H CF CH 94 Me CH(cPr)C₂H₄OMe Me OMe H CF CH 95 Me CH(cBu)C₂H₄OMe Me OMe H CF CH 96 Me CH(Et)C₂H₄OMe Me OMe H CF CH 97 Me CH(Et)Bu Me OMe H CH N 381.1 d 98 Me CHPr2 Me OMe H CH N 381.2 c 99 Me CH(cPr)Et Me OMe H CH N 365.4 c 100 Me CH(cPr)Me Me OMe H CH N 101 Me CH(cPr)Pr Me OMe H CH N 379.1 c 102 Me CH(cBu)Me Me OMe H CH N 103 Me CH(cBu)Et Me OMe H CH N 104 Me CH(cBu)Pr Me OMe H CH N 105 Me CH(Me)CH₂OMe Me OMe H CH N 355.6 d 106 Me CH(Et)CH₂OMe Me OMe H CH N 107 Me CH(cPr)CH₂OMe Me OMe H CH N 108 Me CH(cBu)CH₂OMe Me OMe H CH N 109 Me CH(nPr)CH₂OMe Me OMe H CH N 110 Me CH(cPr)C₂H₄OMe Me OMe H CH N 111 Me CH(cBu)C₂H₄OMe Me OMe H CH N 112 Me CH(Et)C₂H₄OMe Me OMe H CH N 113 Me CH(Me)Et Cl OCHF₂ H CH CH 394.2 c 114 Me CHPr2 Cl OCHF₂ H CH CH 115 Me CH(cPr)Et Cl OCHF₂ H CH CH 420.2 b 116 Me CH(cPr)Me Cl OCHF₂ H CH CH 117 Me CH(cPr)Pr Cl OCHF₂ H CH CH 434.1 b 118 Me CH(cBu)Me Cl OCHF₂ H CH CH 119 Me CH(cBu)Et Cl OCHF₂ H CH CH 120 Me CH(cBu)Pr Cl OCHF₂ H CH CH 121 Me CH(Me)CH₂OMe Cl OCHF₂ H CH CH 410.0 c 122 Me CH(Et)CH₂OMe Cl OCHF₂ H CH CH 424.1 b 123 Me CH(cPr)CH₂OMe Cl OCHF₂ H CH CH 124 Me CH(cBu)CH₂OMe Cl OCHF₂ H CH CH 125 Me CH(nPr)CH₂OMe Cl OCHF₂ H CH CH 126 Me CH(cPr)C₂H₄OMe Cl OCHF₂ H CH CH 127 Me CH(cBu)C₂H₄OMe Cl OCHF₂ H CH CH 128 Me CH(Et)C₂H₄OMe Cl OCHF₂ H CH CH 129 Me CHEt2 Cl CF₃ H CH CH 130 Me CHPr2 Cl CF₃ H CH CH 131 Me CH(cPr)Et Cl CF₃ H CH CH 421.8 c 132 Me CH(cPr)Me Cl CF₃ H CH CH 133 Me CH(cPr)Pr Cl CF₃ H CH CH 134 Me CH(cBu)Me Cl CF₃ H CH CH 135 Me CH(cBu)Et Cl CF₃ H CH CH 136 Me CH(cBu)Pr Cl CF₃ H CH CH 137 Me CH(Me)CH₂OMe Cl CF₃ H CH CH 411.8 c 138 Me CH(Et)CH₂OMe Cl CF₃ H CH CH 425.8 c 139 Me CH(cPr)CH₂OMe Cl CF₃ H CH CH 140 Me CH(CBU)CH₂OMe Cl CF₃ H CH CH 141 Me CH(nPr)CH₂OMe Cl CF₃ H CH CH 142 Me CH(CPr)C₂H₄OMe Cl CF₃ H CH CH 143 Me CH(cBu)C₂H₄OMe Cl CF₃ H CH CH 144 Me CH(Et)C₂H₄OMe Cl CF₃ H CH CH 145 Me CHEt2 Cl OEt H CH CH 146 Me CHPr2 Cl OEt H CH CH 147 Me CH(cPr)Et Cl OEt H CH CH 148 Me CH(cPr)Me Cl OEt H CH CH 149 Me CH(cPr)Pr Cl OEt H CH CH 150 Me CH(cBu)Me Cl OEt H CH CH 151 Me CH(cBu)Et Cl OEt H CH CH 152 Me CH(cBu)Pr Cl OEt H CH CH 153 Me CH(Me)CH₂OMe Cl OEt H CH CH 154 Me CH(Et)CH₂OMe Cl OEt H CH CH 155 Me CH(cPr)CH₂OMe Cl OEt H CH CH 156 Me CHCcBu)CH₂OMe Cl OEt H CH CH 157 Me CH(r1Pr)CH₂OMe Cl OEt H CH CH 158 Me CH(cPr)C₂H₄OMe Cl OEt H CH CH 159 Me CH(cBu)C₂H₄OMe Cl OEt H CH CH 160 Me CH(Et)C₂H₄OMe Cl OEt H CH CH 161 Me CHEt2 Cl OiPr H CH CH 162 Me CHPr2 Cl OiPr H CH CH 163 Me CH(cPr)Et Cl OiPr H CH CH 164 Me CH(cPr)Me Cl OiPr H CH CH 165 Me CH(cPr)Pr Cl OiPr H CH CH 166 Me CH(cBu)Me Cl OiPr H CH CH 167 Me CH(cBu)Et Cl OiPr H CH CH 168 Me CH(cBu)Pr Cl OiPr H CH CH 169 Me CH(Me)CH₂OMeCl OiPr H CH CH 170 Me CH(Et)CH₂OMeCl OiPr H CH CH 171 Me CH(cPr)CH₂OMe Cl OiPr H CH CH 172 Me CH(cBu)CH₂OMe Cl OiPr H CH CH 173 Me CH(nPr)CH₂OMe Cl OiPr H CH CH 174 Me CH(CPr)C₂H₄OMe Cl OiPr H CH CH 175 Me CH(cBu)C₂H₄OMe Cl OiPr H CH CH 176 Me CH(Et)C₂H₄OMe Cl OiPr H CH CH 177 Me CHEt2 CF₃ OMe H CH CH 178 Me CHPr2 CF₃ OMe H CH CH 179 Me CH(cPr)Et CF₃ OMe H CH CH 180 Me CH(cPr)Me CF₃ OMe H CH CH 181 Me CH(cPr)Pr CF₃ OMe H CH CH 182 Me CH(cBu)Me CF₃ OMe H CH CH 183 Me CH(cBu)Et CF₃ OMe H CH CH 184 Me CH(cBu)Pr CF₃ OMe H CH CH 185 Me CH(Me)CH₂OMe CF₃ OMe H CH CH 186 Me CH(Et)CH₂OMe CF₃ OMe H CH CH 187 Me CH(cPr)CH₂OMe CF₃ OMe H CH CH 188 Me CH(cBu)CH₂OMe CF₃ OMe H CH CH 189 Me CH(nPr)CH₂OMe CF₃ OMe H CH CH 190 Me CH(cPr)C₂H₄OMe CF₃ OMe H CH CH 191 Me CH(cBu)C₂H₄OMe CF₃ OMe H CH CH 192 Me CH(Et)C₂H₄OMe CF₃ OMe H CH CH 193 Me CHEt₂ Me OMe H N CH 194 Me CHPr2 Me OMe H N CH 195 Me CH(cPr)Et Me OMe H N CH 196 Me CH(cPr)Me Me OMe H N CH 197 Me CH(cPr)Pr Me OMe H N CH 198 Me CH(cBu)Me Me OMe H N CH 199 Me CH(cBu)Et Me OMe H N CH 200 Me CH(cBu)Pr Me OMe H N CH 201 Me CH(Me)CH₂OMe Me OMe H N CH 202 Me CH(Et)CH₂OMe Me OMe H N CH 203 Me CH(cPr)CH₂OMe Me OMe H N CH 204 Me CH(cBu)CH₂OMe Me OMe H N CH 205 Me CH(nPr)CH₂OMe Me OMe H N CH 206 Me CH(cPr)C₂H₄OMe Me OMe H N CH 207 Me CH(cBu)C₂H₄OMe Me OMe H N CH 208 Me CH(Et)C₂H₄OMe Me OMe H N CH 209 Et CHEt2 Cl Cl H CH CH 210 Et CHPr2 Cl Cl H CH CH 211 Et CH(cPr)Et Cl Cl H CH CH 212 Et CH(cPr)Me Cl Cl H CH CH 213 Et CH(cPr)Pr Cl Cl H CH CH 214 Et CH(cBu)Me Cl Cl H CH CH 215 Et CH(cBu)Et Cl Cl H CH CH 216 Et CH(cBu)Pr Cl Cl H CH CH 217 Et CH(Me)CH₂OMe Cl Cl H CH CH 218 Et CH(Et)CH₂OMe Cl Cl H CH CH 219 Et CH(cPr)CH₂OMe Cl Cl H CH CH 220 Et CH(cBu)CH₂OMe Cl Cl H CH CH 221 Et CH(nPr)CH₂OMe Cl Cl H CH CH 222 Et CH(cPr)C₂H₄OMe Cl Cl H CH CH 223 Et CH(cBu)C₂H₄OMe Cl Cl H CH CH 224 Et CH(Et)C₂H₄OMe Cl Cl H CH CH 225 Et CHEt2 Cl OMe H CH CH 226 Et CHPr2 Cl OMe H CH CH 227 Et CH(cPr)Et Cl OMe H CH CH 228 Et CH(cPr)Me Cl OMe H CH CH 229 Et CH(cPr)Pr Cl OMe H CH CH 230 Et CH(cBu)Me Cl OMe H CH CH 231 Et CH(cBu)Et Cl OMe H CH CH 232 Et CH(cBu)Pr Cl OMe H CH CH 233 Et CH(Me)CH₂OMe Cl OMe H CH CH 234 Et CH(Et)CH₂OMe Cl OMe H CH CH 235 Et CH(cPr)CH₂OMe Cl OMe H CH CH 236 Et CH(cBu)CH₂OMe Cl OMe H CH CH 237 Et CH(nPr)CH₂OMe Cl OMe H CH CH 238 Et CH(cPr)C₂H₄OMe Cl OMe H CH CH 239 Et CH(cBu)C₂H₄OMe Cl OMe H CH CH 240 Et CH(Et)C₂H₄OMe Cl OMe H CH CH 243 Et CH(cPr)Et Cl OMe H CF CH 402.2 a 244 Et CH(cPr)Me Cl OMe H CF CH 245 Et CH(cPr)Pr Cl OMe H CF CH 246 Et CH(cBu)Me Cl OMe H CF CH 247 Et CH(cBu)Et Cl OMe H CF CH 248 Et CH(cBu)Pr Cl OMe H CF CH 249 Et CH(Me)CH₂OMe Cl OMe H CF CH 250 Et CH(Et)CH₂OMe Cl OMe H CF CH 406.3 b 251 Et CH(cPr)CH₂OMe Cl OMe H CF CH 252 Et CH(cBu)CH₂OMe Cl OMe H CF CH 253 Et CH(cPr)CH₂OMe Cl OMe H CF CH 254 Et CH(cPr)C₂H₄OMe Cl OMe H CF CH 255 Et CH(cBu)C₂H₄OMe Cl OMe H CF CH 256 Et CH(Et)C₂H₄OMe Cl OMe H CF CH 257 Et CHFt2 Cl Me H CH CH 258 Et CHPr2 Cl Me H CH CH 259 Et CH(cPr)Et Cl Me H CH CH 260 Et CH(cPr)Me Cl Me H CH CH 261 Et CH(cPr)Pr Cl Me H CH CH 262 Et CH(cBu)Me Cl Me H CH CH 263 Et CH(cBu)Et Cl Me H CH CH 264 Et CH(cBu)Pr Cl Me H CH CH 265 Et CH(Me)CH₂OMe Cl Me H CH CH 266 Et CH(Et)CH₂OMe Cl Me H CH CH 267 Et CH(cPr)CH₂OMe Cl Me H CH CH 268 Et CH(cBu)CH₂OMe Cl Me H CH CH 269 Et CH(nPr)CH₂OMe Cl Me H CH CH 270 Et CH(cPr)C₂H₄OMe Cl Me H CH CH 271 Et CH(cBu)C₂H₄OMe Cl Me H CH CH 272 Et CH(Et)C₂H₄OMe Cl Me H CH CH 273 Et CHEt2 Me OMe H CH CH 274 Et CHPr2 Me OMe H CH CH 275 Et CH(cPr)Et Me OMe H CH CH 276 Et CH(cPr)Me Me OMe H CH CH 277 Et CH(cPr)Pr Me OMe H CH CH 278 Et CH(cBu)Me Me OMe H CH CH 279 Et CH(cBu)Et Me OMe H CH CH 280 Et CH(cBu)Pr Me OMe H CH CH 281 Et CH(Me)CH₂OMe Me OMe H CH CH 282 Et CH(Et)CH₂OMe Me OMe H CH CH 283 Et CH(cPr)CH₂OMe Me OMe H CH CH 284 Et CH(cBu)CH₂OMe Me OMe H CH CH 285 Et CH(nPr)CH₂OMe Me OMe H CH CH 286 Et CH(cPr)C₂H₄OMe Me OMe H CH CH 287 Et CH(cBu)C₂H₄OMe Me OMe H CH CH 288 Et CH(Et)C₂H₄OMe Me OMe H CH CH 289 Et CH1Et₂ Me OMe H CF CH 290 Et CHPr2 Me OMe H CF CH 291 Et CH(cPr)Et Me OMe H CF CH 292 Et CH(cPr)Me Me OMe H CF CH 293 Et CH(cPr)Pr Me OMe H CF CH 294 Et CH(cBu)Me Me OMe H CF CH 295 Et CH(cBu)Et Me OMe H CF CH 296 Et CH(cBu)Pr Me OMe H CF CH 297 Et CH(Me)CH₂OMe Me OMe H CF CH 298 Et CH(Et)CH₂OMe Me OMe H CF CH 299 Et CH(cPr)CH₂OMe Me OMe H CF CH 300 Et CH(cBu)CH₂OMe Me OMe H CF CH 301 Et CH(nPr)CH₂OMe Me OMe H CF CH 302 Et CH(cPr)C₂H₄OMe Me OMe H CF CH 303 Et CH(cBu)C₂H₄OMe Me OMe H CF CH 304 Et CH(Et)C₂H₄OMe Me OMe H CF CH 305 Et CHEt2 Me OMe H CH N 306 Et CHPr2 Me OMe H CH N 307 Et CH(cPr)Et Me OMe H CH N 308 Et CH(cPr)Me Me OMe H CH N 309 Et CH(cPr)Pr Me OMe H CH N 310 Et CH(cBu)Me Me OMe H CH N 311 Et CH(cBu)Et Me OMe H CH N 312 Et CH(cBu)Pr Me OMe H CH N 313 Et CH(Me)CH₂OMe Me OMe H CH N 314 Et CH(Et)CH₂OMe Me OMe H CH N 315 Et CH(cPr)CH₂OMe Me OMe H CH N 316 Et CH(cBu)CH₂OMe Me OMe H CH N 317 Et CH(nPr)CH₂OMe Me OMe H CH N 318 Et CH(cPr)C₂H₄OMe Me OMe H CH N 319 Et CH(cBu)C₂H₄OMe Me OMe H CH N 320 Et CH(Et)C₂OMe Me OMe H CH N 321 Et CHEt₂ Cl OCHF₂ H CH CH 322 Et CHPr2 Cl OCHF₂ H CH CH 323 Et CH(cPr)Et Cl OCHF₂ H CH CH 324 Et CH(cPr)Me Cl OCHF₂ H CH CH 325 Et CH(cPr)Pr Cl OCHF₂ H CH CH 326 Et CH(cBu)Me Cl OCHF₂ H CH CH 327 Et CH(cBu)Et Cl OCHF₂ H CH CH 328 Et CH(cBu)Pr Cl OCHF₂ H CH CH 329 Et CH(Me)CH₂OMe Cl OCHF₂ H CH CH 330 Et CH(Et)CH₂OMe Cl OCHF₂ H CH CH 331 Et CH(cPr)CH₂OMe Cl OCHF₂ H CH CH 332 Et CH(cBu)CH₂OMe Cl OCHF₂ H CH CH 333 Et CH(nPr)CH₂OMe Cl OCHF₂ H CH CH 334 Et CH(cPr)C₂H₄OMe Cl OCHF₂ H CH CH 335 Et CH(cBu)C₂H₄OMe Cl OCHF₂ H CH CH 336 Et CH(Et)C₂H₄OMe Cl OCHF₂ H CH CH 337 Et CHEt2 Cl CF₃ H CH CH 338 Et CHPr2 Cl CF₃ H CH CH 339 Et CH(cPr)Et Cl CF₃ H CH CH 340 Et CH(cPr)Me Cl CF₃ H CH CH 341 Et CH(cPr)Pr Cl CF₃ H CH CH 342 Et CH(cBu)Me Cl CF₃ H CH CH 343 Et CH(cBu)Et Cl CF₃ H CH CH 344 Et CH(cBu)Pr Cl CF₃ H CH CH 345 Et CH(Me)CH₂OMe Cl CF₃ H CH CH 346 Et CH(Et)CH₂OMe Cl CF₃ H CH CH 347 Et CH(cPr)CH₂OMe Cl CF₃ H CH CH 348 Et CH(cBu)CH₂OMe Cl CF₃ H CH CH 349 Et CH(nPr)CH₂OMe Cl CF₃ H CH CH 350 Et CH(cPr)C₂H₄OMe Cl CF₃ H CH CH 351 Et CH(cBu)C₂OMe Cl CF₃ H CH CH 352 Et CH(Et)C₂H₄OMe Cl CF₃ H CH CH 353 Et CHEt₂ Cl OEt H CH CH 354 Et CHPr2 Cl OEt H CH CH 355 Et CH(cPr)Et Cl OEt H CH CH 356 Et CH(cPr)Me Cl OEt H CH CH 357 Et CH(cPr)Pr Cl OEt H CH CH 358 Et CH(cBu)Me Cl OEt H CH CH 359 Et CH(cBu)Et Cl OEt H CH CH 360 Et CH(cBu)Pr Cl OEt H CH CH 361 Et CH(Me)CH₂OMe Cl OEt H CH CH 362 Et CH(Et)CH₂OMe Cl OEt H CH CH 363 Et CH(cPr)CH₂OMe Cl QEt H CH CH 364 Et CH(c13u)CH₂OMe Cl OEt H CH CH 365 Et CH(nPr)CH₂OMe Cl OEt H CH CH 366 Et CH(cPr)C₂H₄OMe Cl OEt H CH CH 367 Et CH(cBu)C₂H₄OMe Cl OEt H CH CH 368 Et CH(Et)C₂H₄OMe Cl OEt H CH CH 369 Et CHEt₂ Cl OiPr H CH CH 370 Et CHPr2 Cl OiPr H CH CH 371 Et CH(cPr)Et Cl OiPr H CH CH 372 Et CH(cPr)Me Cl OiPr H CH CH 373 Et CH(cPr)Pr Cl OiPr H CH CH 374 Et CH(cBu)Me Cl OiPr H CH CH 375 Et CH(cBu)Et Cl OiPr H CH CH 376 Et CH(cBu)Pr Cl OiPr H CH CH 377 Et CH(Me)CH₂OMe Cl OiPr H CH CH 378 Et CH(Et)CH₂OMe Cl OiPr H CH CH 379 Et CH(cPr)CH₂OMe Cl OiPr H CH CH 380 Et CH(cBu)CH₂OMe Cl OiPr H CH CH 381 Et CH(nPr)CH₂OMe ci OiPr H CH CH 382 Et CH(cPr)C₂H₄OMe Cl OiPr H CH CH 383 Et CH(cBu)C₂H₄OMe Cl OiPr H CH CH 384 Et CH(Et)C₂H₄OMe Cl OiPr H CH CH 385 Et CHEt₂ CF₃ OMe H CH CH 386 Et CHPr2 CF₃ OMe H CH CH 387 Et CH(cPr)Et CF₃ OMe H CH CH 388 Et CH(cPr)Me CF₃ OMe H CH CH 389 Et CH(cPr)Pr CF₃ OMe H CH CH 390 Et CH(cBu)Me CF₃ OMe H CH CH 391 Et CH(cBu)Et CF₃ OMe H CH CH 392 Et CH(cBu)Pr CF₃ OMe H CH CH 393 Et CH(Me)CH₂OMeCF₃ OMe H CH CH 394 Et CH(Et)CH₂OMeCF₃ OMe H CH CH 395 Et CH(cPr)CH₂OMe CF₃ OMe H CH CH 396 Et CH(cBu)CH₂OMe CF₃ OMe H CH CH 397 Et CH(nPr)CH₂OMe CF₃ OMe H CH CH 398 Et CH(cPr)C₂H₄OMe CF₃ OMe H CH CH 399 Et CH(cBu)C₂H₄OMe CF₃ OMe H CH CH 400 Et CH(Et)C₂H₄OMe CF₃ OMe H CH CH 401 Et CHEt₂ Me OMe H N CH 402 Et CHPr2 Me OMe H N CH 403 Et CH(cPr)Et Me OMe H N CH 404 Et CH(cPr)Me Me OMe H N CH 405 Et CH(cPr)Pr Me OMe H N CH 406 Et CH(cBu)Me Me OMe H N CH 407 Et CH(cBu)Et Me OMe H N CH 408 Et CH(cBu)Pr Me OMe H N CH 409 Et CH(Me)CH₂OMe Me OMe H N CH 410 Et CH(Et)CH₂OMe Me OMe H N CH 411 Et CH(cPr)CH₂OMe Me OMe H N CH 412 Et CH(cBu)CH₂OMe Me OMe H N CH 413 Et CH(niPr)CH₂OMe Me OMe H N CH 414 Et CH(cPr)C₂H₄OMe Me OMe H N CH 415 Et CH(cBu)C₂H₄OMe Me OMe H N CH 416 Et CH(Et)C₂H₄OMe Me OMe H N CH 417 Et CHEt₂ Cl CN H CH CH 418 Et CHPr2 Cl CN H CH CH 419 Et CH(cPr)Et Cl CN H CH CH 420 Et CH(cPr)Me Cl CN H CH CH 421 Et CH(cPr)Pr Cl CN H CH CH 422 Et CH(cBu)Me Cl CN H CH CH 423 Et CH(cBu)Et Cl CN H CH CH 424 Et CH(cBu)Pr Cl CN H CH CH 425 Et CH(Me)CH₂OMe Cl CN H CH CH 426 Et CH(Et)CH₂OMe Cl CN H CH CH 382.8 e 427 Et CH(cPr)CH₂OMe Cl CN H CH CH 428 Et CH(cBu)CH₂OMe Cl CN H CH CH 429 Et CH(nPr)CH₂OMe Cl CN H CH CH 430 Et CH(cPr)C₂H₄OMe Cl CN H CH CH 431 Et CH(cBu)C₂H₄OMe Cl CN H CH CH 432 Et CH(Et)C₂H₄OMe Cl CN H CH CH 433 Et CHEt₂ Cl CN H CH N 434 Et CHPr2 Cl CN H CH N 435 Et CH(cPr)Et Cl CN H CH N 436 Et CH(cPr)Me Cl CN H CH N 437 Et CH(cPr)Pr Cl CN H CH N 438 Et CH(cBu)Me Cl CN H CH N 439 Et CH(cBu)Et Cl CN H CH N 440 Et CH(cBu)Pr Cl CN H CH N 441 Et CH(Me)CH₂OMe Cl CN H CH N 442 Et CH(Et)CH₂OMe Cl CN H CH N 443 Et CH(cPr)CH₂OMe Cl CN H CH N 444 Et CH(cBu)CH₂OMe Cl CN H CH N 445 Et CH(nPr)CH₂OMe Cl CN H CH N 446 Et CH(cPr)C₂OMe Cl CN H CH N 447 Et CH(cBu)C₂H₄OMe Cl CN H CH N 448 Et CH(Et)C₂H₄OMe Cl CN H CH N 449 Me CH(Et)CH₂OMe Cl CN H CH CH 382.9 e 450 Me CH₂iPr Me OMe H CCl CH 451 Me CH(Me)Pr Me OMe H CCl CH 452 Me CH(cPr)Et Me OMe H CCl CH 400.2 a 453 Me CH(cPr)Me Me OMe H CCl CH 454 Me CH(cPr)Pr Me OMe H CCl CH 455 Me CH(cBu)Me Me OMe H CCl CH 456 Me CH(cBu)Et Me OMe H CCl CH 457 Me CH(cBu)Pr Me OMe H CCl CH 458 Me CH(Me)CH₂OMe Me OMe H CCl CH 459 Me CH(Et)CH₂OMe Me OMe H CCl CH 402.2 b 460 Me CH(cPr)CH₂OMe Me OMe H CCl CH 461 Me CH(cBu)CH₂OMe Me OMe H CCl CH 462 Me CH(nPr)CH₂OMe Me OMe H CCl CH 463 Me CH(cPr)C₂H₄OMe Me OMe H CCl CH 464 Me CH(cBu)C₂H₄OMe Me OMe H CCl CH 465 Me CH(Et)C₂H₄OMe Me OMe H CCl CH 466 Me CH₂iPr Me OMe H CMe CH 467 Me CH(Me)Pr Me OMe H CMe CH c 468 Me CH(cPr)Et Me OMe H CMe CH 469 Me CH(cPr)Me Me OMe H CMe CH 470 Me CH(cPr)Pr Me OMe H CMe CH 471 Me CH(cBu)Me Me OMe H CMe CH 472 Me CH(cBu)Et Me OMe H CMe CH 473 Me CH(cBu)Pr Me OMe H CMe CH 474 Me CH(Me)CH₂OMe Me OMe H CMe CH 475 Me CH(Et)CH₂OMe Me OMe H CMe CH 476 Me CH(cPr)CH₂OMe Me OMe H CMe CH 477 Me CH(cBu)CH₂OMe Me OMe H CMe CH 478 Me CH(nPr)CH₂OMe Me OMe H CMe CH 479 Me CH(cPr)C₂H₄OMe Me OMe H CMe CH 480 Me CH(cBu)C₂OMe Me OMe H CMe CH 481 Me CH(Et)C₂H₄OMe Me OMe H CMe CH 482 Me CH₂iPr Cl OMe H OMe CH 483 Me CH(Me)Pr Cl OMe H CMe CH 484 Me CH(cPr)Et Cl OMe H CMe CH 398.2 a 485 Me CH(cPr)Me Cl OMe H CMe CH 486 Me CH(cPr)Pr Cl OMe H CMe CH 487 Me CH(cBu)Me Cl OMe H CMe CH 488 Me CH(cBu)Et Cl OMe H CMe CH 489 Me CH(cBu)Pr Cl OMe H CMe CH 490 Me CH(Me)CH2OMe Cl OMe H CMe CH 491 Me CH(Et)CH₂OMe Cl OMe H CMe CH 402.2 a 492 Me CH(CPr)CH₂OMe Cl OMe H CMe CH 493 Me CH(cBu)CH₂OMe Cl OMe H CMe CH 494 Me CH(nPr)CH₂OMe Cl OMe H CMe CH 495 Me CH(cPr)C₂H₄OMe Cl OMe H CMe CH 496 Me CH(cBu)C₂H₄OMe Cl OMe H CMe CH 497 Me CH(Et)C₂H₄OMe Cl OMe H CMe CH 498 Me CH₂iPr Cl NMe2 H CF CH 499 Me CH(Me)Pr Cl NMe2 H CF CH 500 Me CH(cPr)Et Cl NMe2 H CF CH 415.3 a 501 Me CH(cPr)Me Cl NMe2 H CF CH 401.2 b 502 Me CH(cPr)Pr Cl NMe2 H CF CH 503 Me CH(cBu)Me Cl NMe2 H CF CH 415.2 b 504 Me CH(cBu)Et Cl NMe2 H CF CH 505 Me CH(cBu)Pr Cl NMe2 H CF CH 506 Me CH(Me)CH₂OMe Cl NMe2 H CF CH 405.2 b 507 Me CH(Et)CH₂OMe Cl NMe2 H CF CH 419.3 a 508 Me CH(cPr)CH₂OMe Cl NMe2 H CF CH 509 Me CH(cBu)CH₂OMe Cl NMe2 H CF CH 510 Me CH(cPr)CH₂OMe Cl NMe2 H CF CH 511 Me CH(cPr)C₂H₄OMe Cl NMe2 H CF CH 512 Me CH(cBu)C₂H₄OMe Cl NMe2 H CF CH 513 Me CH(Et)C₂H₄OMe Cl NMe2 H CF CH 514 Me CH₂iPr Cl OCF₃ H CH CH 515 Me CH(Me)Pr Cl OCF₃ H CH CH 425.2 d 516 Me CH(cPr)Et Cl OCF₃ H CH CH 439.2 c 517 Me CH(cPr)Me Cl OCF₃ H CH CH 518 Me CH(cPr)Pr Cl OCF₃ H CH CH 519 Me CH(cBu)Me Cl OCF₃ H CH CH 520 Me CH(cBu)Et Cl OCF₃ H CH CH 521 Me CH(cBu)Pr Cl OCF₃ H CH CH 522 Me CH(Me)CH₂OMe Cl OCF₃ H CH CH 429.2 d 523 Me CH(Et)CH₂OMe Cl OCF₃ H CH CH 524 Me CH(cPr)CH₂OMe Cl OCF₃ H CH CH 525 Me CH(cBu)CH₂OMe Cl OCF₃ H CH CH 526 Me CH(nPr)CH₂OMe Cl OCF₃ H CH CH 527 Me CH(cPr)C₂H₄OMe Cl OCF₃ H CH CH 528 Me CH(CBu)C₂H₄OMe Cl OCF₃ H CH CH 529 Me CH(Et)C₂H₄OMe Cl OCF₃ H CH CH 530 Me CH₂iPr OMe OMe H N N 531 Me CH(Me)Pr OMe OMe H N N 532 Me CH(cPr)Et OMe OMe H N N 382.4 e 533 Me CH(cPr)Me OMe OMe H N N 534 Me CH(cPr)Pr OMe OMe H N N 535 Me CH(cBu)Me OMe OMe H N N 536 Me CH(cBu)Et OMe OMe H N N 537 Me CH(cBu)Pr OMe OMe H N N 538 Me CH(Me)CH₂OMe OMe OMe H N N 372.4 e 539 Me CH(Et)CH₂OMe OMe OMe H N N 540 Me CH(cPr)CH₂OMe OMe OMe H N N 541 Me CH(cBu)CH₂OMe OMe OMe H N N 542 Me CH(nPr)CH₂OMe OMe OMe H N N 543 Me CH(cPr)C₂H₄OMe OMe OMe H N N 544 Me CH(cBu)C₂H₄OMe OMe OMe H N N 545 Me CH(Et)C₂H₄OMe OMe OMe H N N

[0292] TABLE 2

MS IC₅₀ Ex. # R¹ R³ R^(A) R^(B) R^(C) Y Z (m/z) Range* 546 Me CHMeEt Cl Cl H CH CH 363.1 d 547 Me Cl Cl H CH CH 405.1 d 548 Me CH(cPr)Et Cl Cl H CH CH 389.1 c 549 Me CH(cPr)Me Cl Cl H CH CH 550 Me CH(cPr)Pr Cl Cl H CH CH 551 Me CH(cBu)Me Cl Cl H CH CH 552 Me CH(cBu)Et Cl Cl H CH CH 403.1 c 553 Me CH(cBu)Pr Cl Cl H CH CH 554 Me CH(Me)CH₂OMe Cl Cl H CH CH 379.1 d 555 Me CH(Et)CH₂OMe Cl Cl H CH CH 393.0 556 Me CH(cPr)CH₂OMe Cl Cl H CH CH 557 Me CH(cBu)CH₂OMe Cl Cl H CH CH 558 Me CH(nPr)CH₂OMe Cl Cl H CH CH 559 Me CH(cPr)C₂H₄OMe Cl Cl H CH CH 560 Me CH(cBu)C₂H₄OMe Cl Cl H CH CH 561 Me CH(Et)C₂H₄OMe Cl Cl H CH CH 562 Me CHEt₂ Cl OMe H CH CH 563 Me CHPr2 Cl OMe H CH CH 401.3 b 564 Me CH(cPr)Et Cl OMe H CH CH 385.1 c 565 Me CH(cPr)Me Cl OMe H CH CH 371.3 c 566 Me CH(cPr)Pr Cl OMe H CH CH 567 Me CH(cBu)Me Cl OMe H CH CH 385.3 b 568 Me CH(cBu)Et Cl OMe H CH CH 569 Me CH(cBu)Pr Cl OMe H CH CH 570 Me CH(MC)CH₂OMe Cl OMe H CH CH 375.2 d 571 Me CH(Et)CH₂OMe Cl OMe H CH CH 389.3 c 572 Me CH(cPr)CH₂OMe Cl OMe H CH CH 573 Me CH(cBu)CH₂OMe Cl OMe H CH CH 574 Me CH(cPr)CH₂OMe Cl OMe H CH CH 403.4 d 575 Me CH(cPr)C₂H₄OMe Cl OMe H CH CH 576 Me CH(cBu)C₂H₄OMe Cl OMe H CH CH 577 Me CH(Et)C₂H₄OMe Cl OMe H CH CH 578 Me CHEt₂ Cl OMe H CF CH 579 Me CHPr2 Cl OMe H CF CH 580 Me CH(cPr)Et Cl OMe H CF CH 581 Me CH(cPr)Me Cl OMe H CF CH 582 Me CH(cPr)Pr Cl OMe H CF CH 583 Me CH(cBu)Me Cl OMe H CF CH 584 Me CH(cBu)Et Cl OMe H CF CH 585 Me CH(cBu)Pr Cl OMe H CF CH 586 Me CH(Me)CH₂OMe Cl OMe H CF CH 587 Me CH(Et)CH₂OMe Cl OMe H CF CH 588 Me CH(cPr)CH₂OMe Cl OMe H CF CH 589 Me CH(cBu)CH₂OMe Cl OMe H CF CH 590 Me CH(nPr)CH₂OMe Cl OMe H CF CH 591 Me CH(cPr)C₂H₄OMe Cl OMe H CF CH 592 Me CH(cBu)C₂H₄OMe Cl OMe H CF CH 593 Me CH(Et)C₂H₄OMe Cl OMe H CF CH 594 Me CHEt₂ Cl Me H CH CH 595 Me CHPr2 Cl Me H CH CH 596 Me CH(cPr)Et Cl Me H CH CH 597 Me CH(cPr)Me Cl Me H CH CH 598 Me CH(cPr)Pr Cl Me H CH CH 599 Me CH(cBu)Me Cl Me H CH CH 600 Me CH(cBu)Et Cl Me H CH CH 601 Me CH(cBu)Pr Cl Me H CH CH 602 Me CH(Me)CH₂OMe Cl Me H CH CH 603 Me CH(Et)CH₂OMe Cl Me H CH CH 604 Me CH(cPr)CH₂OMe Cl Me H CH CH 605 Me CH(cBu)CH₂OMe Cl Me H CH CH 606 Me CH(nPr)CH₂OMe Cl Me H CH CH 607 Me CH(cPr)C₂H₄OMe Cl Me H CH CH 608 Me CH(CBu)C₂H₄OMe Cl Me H CH CH 609 Me CH(Et)C₂H₄OMe Cl Me H CH CH 610 Me CHEt₂ Me OMe H CH CH 611 Me CHPr2 Me OMe H CH CH 612 Me CH(cPr)Et Me OMe H CH CH 377.3 d 613 Me CH(cPr)Me Me OMe H CH CH 614 Me CH(cPr)Pr Me OMe H CH CH 615 Me CH(cBu)Me Me OMe H CH CH 616 Me CH(cBu)Et Me OMe H CH CH 617 Me CH(cBu)Pr Me OMe H CH CH 618 Me CH(Me)CH₂OMe Me OMe H CH CH 619 Me CH(Et)CH₂OMe Me OMe H CH CH 620 Me CH(cPr)CH₂OMe Me OMe H CH CH 621 Me CH(cBu)CH₂OMe Me OMe H CH CH 622 Me CH(flPr)CH₂OMe Me OMe H CH CH 623 Me CH(cPr)C₂H₄OMe Me OMe H CH CH 624 Me CH(CBu)C₂H₄OMe Me OMe H CH CH 625 Me CH(Et)C₂H₄OMe Me OMe H CH CH 626 Me CHEt₂ Me OMe H CF CH 627 Me CHPr2 Me OMe H CF CH 628 Me CH(cPr)Et Me OMe H CF CH 629 Me CH(cPr)Me Me OMe H CF CH 630 Me CH(cPr)Pr Me OMe H CF CH 631 Me CH(cBu)Me Me OMe H CF CH 632 Me CH(cBu)Et Me OMe H CF CH 633 Me CH(cBu)Pr Me OMe H CF CH 634 Me CH(Me)CH₂OMe Me OMe H CF CH 635 Me CH(Et)CH₂OMe Me OMe H CF CH 636 Me CH(cPr)CH₂OMe Me OMe H CF CH 637 Me CH(cBu)CH₂OMe Me OMe H CF CH 638 Me CH(nPr)CH₂OMe Me OMe H CF CH 639 Me CH(cPr)C₂H₄OMe Me OMe H CF CH 640 Me CH(cBu)C₂H₄OMe Me OMe H CF CH 641 Me CH(Et)C₂H₄OMe Me OMe H CF CH 642 Me CHEt2 Me OMe H CH N 643 Me CHPr2 Me OMe H CH N 644 Me CH(cPr)Et Me OMe H CH N 366.3 d 645 Me CH(cPr)Me Me OMe H CH N 646 Me CH(cPr)Pr Me OMe H CH N 647 Me CH(cBu)Me Me OMe H CH N 648 Me CH(cBu)Et Me OMe H CH N 649 Me CH(cBu)Pr Me OMe H CH N 650 Me CH(Me)CH₂OMe Me OMe H CH N 356.3 e 651 Me CH(Et)CH₂OMe Me OMe H CH N 370.3 e 652 Me CH(cPr)CH₂OMe Me OMe H CH N 653 Me CH(cBu)CH₂OMe Me OMe H CH N 654 Me CH(nPr)CH₂OMe Me OMe H CH N 655 Me CH(cPr)C₂H₄OMe Me OMe H CH N 656 Me CH(cBu)C₂H₄OMe Me OMe H CH N 657 Me CH(Et)C₂H₄OMe Me OMe H CH N 658 Me CHEt₂ Cl OCHF₂ H CH CH 659 Me CHPr2 Cl OCHF₂ H CH CH 660 Me CH(cPr)Et Cl OCHF₂ H CH CH 661 Me CH(cPr)Me Cl OCHF₂ H CH CH 662 Me CH(cPr)Pr Cl OCHF₂ H CH CH 663 Me CH(cBu)Me Cl OCHF₂ H CH CH 664 Me CH(cBu)Et Cl OCHF₂ H CH CH 665 Me CH(cBu)Pr Cl OCHF₂ H CH CH 666 Me CH(Me)CH₂OMe Cl OCHF₂ H CH CH 667 Me CH(Et)CH₂OMe Cl OCHF₂ H CH CH 668 Me CH(cPr)CH₂OMe Cl OCHF₂ H CH CH 669 Me CH(cBu)CH₂OMe Cl OCHF₂ H CH CH 670 Me CH(nPr)CH₂OMe Cl OCHF₂ H CH CH 671 Me CH(cPr)C₂H₄OMe Cl OCHF₂ H CH CH 672 Me CH(cBu)C₂H₄OMe Cl OCHF₂ H CH CH 673 Me CH(Et)C₂H₄OMe Cl OCHF₂ H CH CH 674 Me CHEt₂ Cl CF₃ H CH CH 675 Me CHPr2 Cl CF₃ H CH CH 676 Me CH(cPr)Et Cl CF₃ H CH CH 677 Me CH(cPr)Me Cl CF₃ H CH CH 678 Me CH(cPr)Pr Cl CF₃ H CH CH 679 Me CH(cBu)Me Cl CF₃ H CH CH 680 Me CH(cBu)Et Cl CF₃ H CH CH 681 Me CH(cBu)Pr Cl CF₃ H CH CH 682 Me CH(Me)CH₂OMe Cl CF₃ H CH CH 683 Me CH(Et)CH₂OMe Cl CF₃ H CH CH 684 Me CH(cPr)CH₂OMe Cl CF₃ H CH CH 685 Me CH(cBu)CH₂OMe Cl CF₃ H CH CH 686 Me CH(nPr)CH₂OMe Cl CF₃ H CH CH 687 Me CH(cPr)C₂H₄OMe Cl CF₃ H CH CH 688 Me CH(cBu)C₂H₄OMe Cl CF₃ H CH CH 689 Me CH(Et)C₂H₄OMe Cl CF₃ H CH CH 690 Me CHEt₂ Cl OEt H CH CH 691 Me CHPr2 Cl OEt H CH CH 692 Me CH(cPr)Et Cl OEt H CH CH 693 Me CH(cPr)Me Cl OEt H CH CH 694 Me CH(cPr)Pr Cl OEt H CH CH 695 Me CH(cBu)Me Cl OEt H CH CH 696 Me CH(cBu)Et Cl OEt H CH CH 697 Me CH(cBu)Pr Cl OEt H CH CH 698 Me CH(MC)CH₂OMe Cl OEt H CH CH 699 Me CH(Et)CH₂OMe Cl OEt H CH CH 700 Me CH(cPr)CH₂OMe Cl OEt H CH CH 701 Me CH(cBu)CH₂OMe Cl OEt H CH CH 702 Me CH(nPr)CH₂OMe Cl OEt H CH CH 703 Me CH(cPr)C₂H₄OMe Cl OEt H CH CH 704 Me CH(cBu)C₂H₄OMe Cl OEt H CH CH 705 Me CH(Et)C₂H₄OMe Cl OEt H CH CH 706 Me CHEt₂ Cl OiPr H CH CH 707 Me CHPr2 Cl OiPr H CH CH 708 Me CH(cPr)Et Cl OiPr H CH CH 709 Me CH(cPr)Me Cl OiPr H CH CH 710 Me CH(cPr)Pr Cl OiPr H CH CH 711 Me CH(cBu)Me Cl OiPr H CH CH 712 Mc CH(cBu)Et Cl OiPr H CH CH 713 Me CH(cBu)Pr Cl OiPr H CH CH 714 Me CH(Me)CH₂OMe Cl OiPr H CH CH 715 Me CH(Et)CH₂OMe Cl OiPr H CH CH 716 Me CH(cPr)CH₂OMe Cl OiPr H CH CH 717 Me CH(cBu)CH₂OMe Cl OiPr H CH CH 718 Me CH(npr)CH₂OMC Cl OiPr H CH CH 719 Me CH(cPr)C₂H₄OMe Cl OiPr H CH CH 720 Me CH(cBu)C₂H₄OMe Cl OiPr H CH CH 721 Me CH(Et)C₂H₄OMeCl OiPr H CH CH 722 Me CHEt₂ CF₃ OMe H CH CH 723 Me CHPr2 CF₃ OMe H CH CH 724 Me CH(cPr)Et CF₃ OMe H CH CH 725 Me CH(cPr)Me CF₃ OMe H CH CH 726 Me CH(cPr)Pr CF₃ OMe H CH CH 727 Me CH(cBu)Me CF₃ OMe H CH CH 728 Me CH(cBu)Et CF₃ OMe H CH CH 729 Me CH(cBu)Pr CF₃ OMe H CH CH 730 Me CH(Me)CH₂OMe CF₃ OMe H CH CH 731 Me CH(Et)CH₂OMe CF₃ OMe H CH CH 732 Me CH(cPr)CH₂OMe CF₃ OMe H CH CH 733 Me CH(cBu)CH₂OMe CF₃ OMe H CH CH 734 Me CH(nPr)CH₂OMe CF₃ OMe H CH CH 735 Me CH(cPr)C₂H₄OMe CF₃ OMe H CH CH 736 Me CH(cBu)C₂H₄OMe CF₃ OMe H CH CH 737 Me CH(Et)C₂H₄OMe CF₃ OMe H CH CH 738 Me CHEt₂ Me OMe H N CH 739 Me CHPr2 Me OMe H N CH 740 Me CH(cPr)Et Me OMe H N CH 741 Me CH(cPr)Me Me OMe H N CH 742 Me CH(cPr)Pr Me OMe H N CH 743 Me CH(cBu)Me Me OMe H N CH 744 Me CH(cBu)Et Me OMe H N CH 745 Me CH(cBu)Pr Me OMe H N CH 746 Me CH(Me)CH₂OMe Me OMe H N CH 747 Me CH(Et)CH₂OMe Me OMe H N CH 748 Me CH(cPr)CH₂OMe Me OMe H N CH 749 Me CH(cBU)CH₂OMe Me OMe H N CH 750 Me CH(nPr)CH₂OMe Me OMe H N CH 751 Me CH(cPr)C₂H₄OMe Me OMe H N CH 752 Me CH(cBU)C₂H₄OMe Me OMe H N CH 753 Me CH(Et)C₂H₄OMe Me OMe H N CH 754 Et CHEt₂ Cl Cl H CH CH 755 Et CHPr2 Cl Cl H CH CH 756 Et CH(cPr)Et Cl Cl H CH CH 757 Et CH(cPr)Me Cl Cl H CH CH 758 Et CH(cPr)Pr Cl Cl H CH CH 759 Et CH(cBu)Me Cl Cl H CH CH 760 Et CH(cBu)Et Cl Cl H CH CH 761 Et CH(cBu)Pr Cl Cl H CH CH 762 Et CH(Me)CH₂OMe Cl Cl H CH CH 763 Et CH(Et)CH₂OMe Cl Cl H CH CH 764 Et CH(cPr)CH₂OMe Cl Cl H CH CH 765 Et CH(cBu)CH₂OMe Cl Cl H CH CH 766 Et CH(nPr)CH₂OMe Cl Cl H CH CH 767 Et CH(cPr)C₂H₄OMe Cl Cl H CH CH 768 Et CH(cBu)C₂H₄OMe Cl Cl H CH CH 769 Et CH(Et)C₂H₄OMe Cl Cl H CH CH 770 Et CHEt₂ Cl OMe H CH CH 771 Et CHPr2 Cl OMe H CH CH 772 Et CH(cPr)Et Cl OMe H CH CH 773 Et CH(cPr)Me Cl OMe H CH CH 774 Et CH(cPr)Pr Cl OMe H CH CH 775 Et CH(cBu)Me Cl OMe H CH CH 776 Et CH(cBu)Et Cl OMe H CH CH 777 Et CH(cBu)Pr Cl OMe H CH CH 778 Et CH(Me)CH₂OMe Cl OMe H CH CH 779 Et CH(Et)CH₂OMe Cl OMe H CH CH 780 Et CH(cPr)CH₂OMe Cl OMe H CH CH 781 Et CH(cBu)CH₂OMe Cl OMe H CH CH 782 Et CH(nPr)CH₂OMe Cl OMe H CH CH 783 Et CH(cPr)C₂H₄OMe Cl OMe H CH CH 784 Et CH(cBu)C₂H₄OMe Cl OMe H CH CH 785 Et CH(Et)C₂H₄OMe Cl OMe H CH CH 786 Et CHEt₂ Cl OMe H CF CH 787 Et CHPr2 Cl OMe H CF CH 788 Et CH(cPr)Et Cl OMe H CF CH 789 Et CH(cPr)Me Cl OMe H CF CH 790 Et CH(cPr)Pr Cl OMe H CF CH 791 Et CH(cBu)Me Cl OMe H CF CH 792 Et CH(cBu)Et Cl OMe H CF CH 793 Et CH(cBu)Pr Cl OMe H CF CH 794 Et CH(Me)CH₂OMe Cl OMe H CF CH 795 Et CH(Et)CH₂OMe Cl OMe H CF CH 796 Et CH(cPr)CH₂OMeCl OMe H CF CH 797 Et CH(cBu)CH₂OMeCl OMe H CF CH 798 Et CH(nPr)CH₂OMeCl OMe H CF CH 799 Et CH(cPr)C₂H₄OMe Cl OMe H CF CH 800 Et CH(cBu)C₂H₄OMe Cl OMe H CF CH 801 Et CH(Et)C₂H₄OMe Cl OMe H CF CH 802 Et CHEt₂ Cl Me H CH CH 803 Et CHPr2 Cl Me H CH CH 804 Et CH(cPr)Et Cl Me H CH CH 805 Et CH(cPr)Me Cl Me H CH CH 806 Et CH(cPr)Pr Cl Me H CH CH 807 Et CH(cBu)Me Cl Me H CH CH 808 Et CH(cBu)Et Cl Me H CH CH 809 Et CH(cBu)Pr Cl Me H CH CH 810 Et CH(Me)CH₂OMe Cl Me H CH CH 811 Et CH(Et)CH₂OMe Cl Me H CH CH 812 Et CH(cPr)CH₂OMeCl Me H CH CH 813 Et CH(cBu)CH₂OMeCl Me H CH CH 814 Et CH(nPr)CH₂OMeCl Me H CH CH 815 Et CH(cPr)C₂H₄OMe Cl Me H CH CH 816 Et CH(cBu)C₂H₄OMe Cl Me H CH CH 817 Et CH(Et)C₂H₄OMe Cl Me H CH CH 818 Et CHEt₂ Me OMe H CH CH 819 Et CHPr2 Me OMe H CH CH 820 Et CH(cPr)Et Me OMe H CH CH 821 Et CH(cPr)Me Me OMe H CH CH 822 Et CH(cPr)Pr Me OMe H CH CH 823 Et CH(cBu)Me Me OMe H CH CH 824 Et CH(cBu)Et Me OMe H CH CH 825 Et CH(cBu)Pr Me OMe H CH CH 826 Et CH(Me)CH₂OMe Me OMe H CH CH 827 Et CH(Et)CH₂OMe Me OMe H CH CH 828 Et CH(cPr)CH₂OMe Me OMe H CH CH 829 Et CH(cBu)CH₂OMe Me OMe H CH CH 830 Et CH(nPr)CH₂OMe Me OMe H CH CH 831 Et CH(cPr)C₂H₄OMe Me OMe H CH CH 832 Et CH(cBu)C2H21OMe Me OMe H CH CH 833 Et CH(Et)C₂H₄OMe Me OMe H CH CH 834 Et CHEt₂ Me OMe H CF CH 835 Et CHPr2 Me OMe H CF CH 836 Et CH(cPr)Et Me OMe H CF CH 837 Et CH(cPr)Me Me OMe H CF CH 838 Et CH(cPr)Pr Me OMe H CF CH 839 Et CH(cBu)Me Me OMe H CF CH 840 Et CH(cBu)Et Me OMe H CF CH 841 Et CH(cBu)Pr Me OMe H CF CH 842 Et CH(Me)CH₂OMe Me OMe H CF CH 843 Et CH(Et)CH₂OMe Me OMe H CF CH 844 Et CH(cPr)CH₂OMe Me OMe H CF CH 845 Et CH(cBu)CH₂OMe Me OMe H CF CH 846 Et CH(nPr)CH₂OMe Me OMe H CF CH 847 Et CH(cPr)C₂H₄OMe Me OMe H CF CH 848 Et CH(cBu)C₂H₄OMe Me OMe H CF CH 849 Et CH(Et)C₂H₄OMe Me OMe H CF CH 850 Et CHEt₂ Me OMe H CH N 851 Et CHPr2 Me OMe H CH N 852 Et CH(cPr)Et Me OMe H CH N 853 Et CH(cPr)Me Me OMe H CH N 854 Et CH(cPr)Pr Me OMe H CH N 855 Et CH(cBu)Me Me OMe H CH N 856 Et CH(cBu)Et Me OMe H CH N 857 Et CH(cBu)Pr Me OMe H CH N 858 Et CH(Me)CH₂OMe Me OMe H CH N 859 Et CH(Et)CH₂OMe Me OMe H CH N 860 Et CH(cPr)CH₂OMeMe OMe H CH N 861 Et CH(cBu)CH₂OMeMe OMe H CH N 862 Et CH(nPr)CH₂OMeMe OMe H CH N 863 Et CH(cPr)C₂H₄OMe Me OMe H CH N 864 Et CH(cBu)C₂H₄OMe Me OMe H CH N 865 Et CH(Et)C₂H₄OMe Me OMe H CH N 866 Et CHEt₂ Cl OCHF₂ H CH CH 867 Et CHPr2 Cl OCHF₂ H CH CH 868 Et CH(cPr)Et Cl OCHF₂ H CH CH 869 Et CH(cPr)Me Cl OCHF₂ H CH CH 870 Et CH(cPr)Pr Cl OCHF₂ H CH CH 871 Et CH(cBu)Me Cl OCHF₂ H CH CH 872 Et CH(cBu)Et Cl OCHF₂ H CH CH 873 Et CH(cBu)Pr Cl OCHF₂ H CH CH 874 Et CH(Me)CH₂OMe Cl OCHF₂ H CH CH 875 Et CH(Et)CH₂OMe Cl OCHF₂ H CH CH 876 Et CH(cPr)CH₂OMe Cl OCHF₂ H CH CH 877 Et CH(cBu)CH₂OMe Cl OCHF₂ H CH CH 878 Et CH(nPr)CH₂OMe Cl OCHF₂ H CH CH 879 Et CH(cPr)C₂H₄OMe Cl OCHF₂ H CH CH 880 Et CH(cBu)C₂H₄OMe Cl OCHF₂ H CH CH 881 Et CH(Et)C₂H₄OMe Cl OCHF₂ H CH CH 882 Et CHEt₂ Cl CF₃ H CH CH 883 Et CHPr2 Cl CF₃ H CH CH 884 Et CH(cPr)Et Cl CF₃ H CH CH 885 Et CH(cPr)Me Cl CF₃ H CH CH 886 Et CH(cPr)Pr Cl CF₃ H CH CH 887 Et CH(cBu)Me Cl CF₃ H CH CH 888 Et CH(cBu)Et Cl CF₃ H CH CH 889 Et CH(cBu)Pr Cl CF₃ H CH CH 890 Et CH(Me)CH₂OMe Cl CF₃ H CH CH 891 Et CH(Et)CH₂OMe Cl CF₃ H CH CH 892 Et CH(cPr)CH₂OMe Cl CF₃ H CH CH 893 Et CH(cBu)CH₂OMe Cl CF₃ H CH CH 894 Et CH(nPr)CH₂OMe Cl CF₃ H CH CH 895 Et CH(cPr)C₂H₄OMe Cl CF₃ H CH CH 896 Et CH(cBu)C₂H₄OMe Cl CF₃ H CH CH 897 Et CH(Et)C₂H₄OMe Cl CF₃ H CH CH 898 Et CHEt₂ Cl OEt H CH CH 899 Et CHPr2 Cl OEt H CH CH 900 Et CH(cPr)Et Cl OEt H CH CH 901 Et CH(cPr)Me Cl OEt H CH CH 902 Et CH(cPr)Pr Cl OEt H CH CH 903 Et CH(cBu)Me Cl OEt H CH CH 904 Et CH(cBu)Et Cl OEt H CH CH 905 Et CH(cBu)Pr Cl OEt H CH CH 906 Et CH(Me)CH₂OMe Cl OEt H CH CH 907 Et CH(Et)CH₂OMe Cl OEt H CH CH 908 Et CH(cPr)CH₂OMe Cl OEt H CH CH 909 Et CH(cBu)CH₂OMe Cl OEt H CH CH 910 Et CH(nPr)CH₂OMe Cl OEt H CH CH 911 Et CH(cPr)C₂H₄OMe Cl OEt H CH CH 912 Et CH(cBu)C₂H₄OMe Cl OEt H CH CH 913 Et CH(Et)C₂H₄OMe Cl OEt H CH CH 914 Et CHEt₂ Cl OiPr H CH CH 915 Et CHPr2 Cl OiPr H CH CH 916 Et CH(cPr)Et Cl OiPr H CH CH 917 Et CH(cPr)Me Cl OiPr H CH CH 918 Et CH(cPr)Pr Cl OiPr H CH CH 919 Et CH(cBu)Me Cl OiPr H CH CH 920 Et CH(cBu)Et Cl OiPr H CH CH 921 Et CH(cBu)Pr Cl OiPr H CH CH 922 Et CH(Me)CH₂OMe Cl OiPr H CH CH 923 Et CH(Et)CH₂OMe C OiPr H CH CH 924 Et CH(cPr)CH₂OMe Cl OiPr H CH CH 925 Et CH(cBu)CH₂OMe Cl OiPr H CH CH 926 Et CH(nPr)CH₂OMe Cl OiPr H CH CH 927 Et CH(cPr)C₂H₄OMe Cl OiPr H CH CH 928 Et CH(cBu)C₂H₄OMe Cl OiPr H CH CH 928 Et CH(Et)C₂H₄OMe Cl OiPr H CH CH 930 Et CHEt₂ CF₃ OMe H CH CH 931 Et CHPr2 CF₃ OMe H CH CH 932 Et CH(cPr)Et CF₃ OMe H CH CH 933 Et CH(cPr)Me CF₃ OMe H CH CH 934 Et CH(cPr)Pr CF₃ OMe H CH CH 935 Et CH(cBu)Me CF₃ OMe H CH CH 936 Et CH(cBu)Et CF₃ OMe H CH CH 937 Et CH(cBu)Pr CF₃ OMe H CH CH 938 Et CH(Me)CH₂OMe CF₃ OMe H CH CH 939 Et CH(Et)CH₂OMe CF₃ OMe H CH CH 940 Et CH(cPr)CH₂OMe CF₃ OMe H CH CH 941 Et CH(cBu)CH₂OMe CF₃ OMe H CH CH 942 Et CH(nIPr)CH₂OMe CF₃ OMe H CH CH 943 Et CH(cPr)C₂H₄OMe CF₃ OMe H CH CH 944 Et CH(cBu)C₂H₄OMe CF₃ OMe H CH CH 945 Et CH(Et)C₂H₄OMe CF₃ OMe H CH CH 946 Et CHEt₂ Me OMe H N CH 947 Et CHPr2 Me OMe H N CH 948 Et CH(cPr)Et Me OMe H N CH 949 Et CH(cPr)Me Me OMe H N CH 950 Et CH(cPr)Pr Me OMe H N CH 951 Et CH(cBu)Me Me OMe H N CH 952 Et CH(cBu)Et Me OMe H N CH 953 Et CH(cBu)Pr Me OMe H N CH 954 Et CH(Me)CH₂OMe Me OMe H N CH 955 Et CH(Et)CH₂OMe Me OMe H N CH 956 Et CH(cPr)CH₂OMe Me OMe H N CH 957 Et CH(cBu)CH₂OMe Me OMe H N CH 958 Et CH(nPr)CH₂OMe Me OMe H N CH 959 Et CH(cPr)C₂H₄OMe Me OMe H N CH 960 Et CH(cBu)C₂H₄OMe Me OMe H N CH 961 Et CH(EQC₂H₄OMe Me OMe H N CH 962 Et CHEt₂ Cl CN H CH CH 963 Et CHPr2 Cl CN H CH CH 964 Et CH(cPr)Et Cl CN H CH CH 965 Et CH(cPr)Me Cl CN H CH CH 966 Et CH(cPr)Pr Cl CN H CH CH 967 Et CH(cBu)Me Cl CN H CH CH 968 Et CH(cBu)Et Cl CN H CH CH 969 Et CH(cBu)Pr Cl CN H CH CH 970 Et CH(Me)CH₂OMe Cl CN H CH CH 971 Et CH(Et)CH₂OMe Cl CN H CH CH 972 Et CH(cPr)CH₂OMe Cl CN H CH CH 973 Et CH(cBu)CH₂OMe Cl CN H CH CH 974 Et CH(nPr)CH₂OMe Cl CN H CH CH 975 Et CH(cPr)C₂H₄OMe Cl CN H CH CH 976 Et CH(cBu)C₂H₄OMe Cl CN H CH CH 977 Et CH(Et)C₂H₄OMe Cl CN H CH CH 978 Et CHEt₂ Cl CN H CH N 979 Et CHFr2 Cl CN H CH N 980 Et CH(cPr)Et Cl CN H CH N 981 Et CH(cPr)Me Cl CN H CH N 982 Et CH(cPr)Pr Cl CN H CH N 983 Et CH(cBu)Me Cl CN H CH N 984 Et CH(cBu)Et Cl CN H CH N 985 Et CH(cBu)Pr Cl CN H CH N 986 Et CH(Me)CH₂OMe Cl CN H CH N 987 Et CH(Et)CH₂OMe Cl CN H CH N 988 Et CH(cPr)CH₂OMe Cl CN H CH N 989 Et CH(cBu)CH₂OMe Cl CN H CH N 990 Et CH(nPr)CH₂OMe Cl CN H CH N 991 Et CH(cPr)C₂H₄OMe Cl CN H CH N 992 Et CH(cBu)C₂H₄OMe Cl CN H CH N 993 Et CH(Et)C₂H₄OMe Cl CN H CH N 994 Me CH(cPr)2 Cl Cl H CH CH 401.1 c 995 Me CH₂iPr Me OMe H CCl CH 996 Me CH(Me)Pr Me OMe H CCl CH 997 Me CH(cPr)Et Me OMe H CCl CH 998 Me CH(cPr)Me Me OMe H CCl CH 999 Me CH(cPr)Pr Me OMe H CCl CH 1000 Me CH(cBu)Me Me OMe H CCl CH 1001 Me CH(cBu)Et Me OMe H CCl CH 1002 Me CH(cBu)Pr Me OMe H CCl CH 1003 Me CH(Me)CH₂OMe Me OMe H CCl CH 1004 Me CH(Et)CH₂OMe Me OMe H CCl CH 1005 Me CH(cPr)CH₂OMe Me OMe H CCl CH 1006 Me CH(cBU)CH₂OMe Me OMe H CCl CH 1007 Me CH(nPr)CH₂OMe Me OMe H CCl CH 1008 Me CH(cPr)C₂H₄OMe Me OMe H CCl CH 1009 Me CH(cBu)C₂H₄OMe Me OMe H CCl CH 1010 Me CH(Et)C₂H₄OMe Me OMe H CCl CH 1011 Me CH₂IPr Me OMe H CMe CH 1012 Me CH(Me)Pr Me OMe H CMe CH 1013 Me CH(cPr)Et Me OMe H CMe CH c 1014 Me CH(cPr)Me Me OMe H CMe CH 1015 Me CH(cPr)Pr Me OMe H CMe CH 1016 Me CH(cBu)Me Me OMe H CMe CH 1017 Me CH(cBu)Et Me OMe H CMe CH 1018 Me CH(cBu)Pr Me OMe H CMe CH 1019 Me CH(Me)CH₂OMe Me OMe H CMe CH 1020 Me CH(Et)CH₂OMe Me OMe H CMe CH 1021 Me CH(cPr)CH₂OMe Me OMe H CMe CH 1022 Me CH(cBu)CH₂OMe Me OMe H CMe CH 1023 Me CH(nPr)CH₂OMe Me OMe H CMe CH 1024 Me CH(cPr)C₂H₄OMe Me OMe H CMe CH 1025 Me CH(cBu)C₂H₄OMe Me OMe H CMe CH 1026 Me CH(Et)C₂H₄OMe Me OMe H CMe CH 1027 Me CH₂iPr Cl OMe H CMe CH 1028 Me CH(Me)Pr Cl OMe H CMe CH 1029 Me CH(cPr)Et Cl OMe H CMe CH 1030 Me CH(cPr)Me Cl OMe H CMe CH 1031 Me CH(cPr)Pr Cl OMe H CMe CH 1032 Me CH(cBu)Me Cl OMe H CMe CH 1033 Me CH(cBu)Et Cl OMe H CMe CH 1034 Me CH(cBu)Pr Cl OMe H CMe CH 1035 Me CH(Me)CH₂OMe Cl OMe H CMe CH 1036 Me CH(Et)CH₂OMe Cl OMe H CMe CH 1037 Me CH(cPr)CH₂OMe Cl OMe H CMe CH 1038 Me CH(cBu)CH₂OMe Cl OMe H CMe CH 1039 Me CH(nPr)CH₂OMe Cl OMe H CMe CH 1040 Me CH(cPr)C₂H₄OMe Cl OMe H CMe CH 1041 Me CH(cBu)C₂H₄OMe Cl OMe H CMe CH 1042 Me CH(Et)C₂H₄OMe Cl OMe H CMe CH 1043 Me CH₂iPr Cl NMe₂ H CF CH 1044 Me CH(Me)Pr Cl NMe₂ H CF CH 1045 Me CH(cPr)Et Cl NMe₂ H CF CH 1046 Me CH(cPr)Me Cl NMe₂ H CF CH 1047 Me CH(cPr)Pr Cl NMe₂ H CF CH 1048 Me CH(cBu)Me Cl NMe₂ H CF CH 1049 Me CH(cBu)Et Cl NMe₂ H CF CH 1050 Me CH(cBu)Pr Cl NMe₂ H CF CH 1051 Me CH(Me)CH₂OMe Cl NMe₂ H CF CH 1052 Me CH(Et)CH₂OMe Cl NMe₂ H CF CH 1053 Me CH(cPr)CH₂OMe Cl NMe₂ H CF CH 1054 Me CH(cBu)CH₂OMe Cl NMe₂ H CF CH 1055 Me CH(niPr)CH₂OMe Cl NMe₂ H CF CH 1056 Me CH(cPr)C₂H₄OMe Cl NMe₂ H CF CH 1057 Me CH(cBu)C₂H₄OMe Cl NMe₂ H CF CH 1058 Me CH(Et)C₂H₄OMe Cl NMe₂ H CF CH 1059 Me CH₂iPr Cl OCF₃ H CH CH 1060 Me CH(Me)Pr Cl OCF₃ H CH CH 1061 Me CH(cPr)Et Cl OCF₃ H CH CH c 1062 Me CH(cPr)Me Cl OCF₃ H CH CH 425.2 d 1063 Me CH(cPr)Pr Cl OCF₃ H CH CH 1064 Me CH(cBu)Me Cl OCF₃ H CH CH 1065 Me CH(cBu)Et Cl OCF₃ H CH CH 1066 Me CH(cBu)Pr Cl OCF₃ H CH CH 1067 Me CH(Me)CH₂OMe Cl OCF₃ H CH CH c 1068 Me CH(Et)CH₂OMe Cl OCF₃ H CH CH 1069 Me CH(cPr)CH₂OMe Cl OCF₃ H CH CH 1070 Me CH(cBu)CH₂OMe Cl OCF₃ H CH CH 1071 Me CH(nPr)CH₂OMe Cl OCF₃ H CH CH 1072 Me CH(cPr)C₂H₄OMe Cl OCF₃ H CH CH 1073 Me CH(cBu)C₂H₄OMe Cl OCF₃ H CH CH 1074 Me CH(Et)C₂H₄OMe Cl OCF₃ H CH CH 1075 Me CH₂iPr OMe OMe H N N 1076 Me CH(Me)Pr OMe OMe H N N 1077 Me CH(cPr)Et OMe OMe H N N 1078 Me CH(cPr)Me OMe OMe H N N 1079 Me CH(cPr)Pr OMe OMe H N N 1080 Me CH(cBu)Me OMe OMe H N N 1081 Me CH(cBu)Et OMe OMe H N N 1082 Me CH(cBu)Pr OMe OMe H N N 1083 Me CH(Me)CH₂OMe OMe OMe H N N 1084 Me CH(Et)CH₂OMe OMe OMe H N N 1085 Me CH(cPr)CH₂OMe OMe OMe H N N 1086 Me CH(cBu)CH₂OMe OMe OMe H N N 1087 Me CH(nPr)CH₂OMe OMe OMe H N N 1088 Me CH(cPr)C₂H₄OMe OMe OMe H N N 1089 Me CH(CBu)C₂H₄OMe OMe OMe H N N 1090 Me CH(Et)C₂H₄OMe OMe OMe H N N

[0293]

PREPARATION 1 2-Chloro-5-fluoro-4-methoxyphenylboronic acid

[0294] Part A

[0295] To a 1-chloro-3,4-difluorobenzene (25 g, 0.17 mol) cooled to 0° C. was added fuming nitric acid (50 mL) dropwise over 30 min. The orange solution was warmed to room temperature and stirred for 2 h. The solution was poured slowly over ice and the resultant mixture extracted with diethyl ether. The diethyl ether layers were washed with brine, dried (Na₂SO₄), filtered and concentrated in vacuo to give 26 g (80%) of 1-chloro-4,5-difluoro-2-nitro-benzene: Crude ¹H NMR (400 MHz, CDCl₃): δ 7.88 (dd, J=9.3, 7.6 Hz, 1H), 7.43 (dd, J=9.3, 7.1 Hz, 1H). The crude material was pure enough to carry on to the next step.

[0296] Part B

[0297] To sodium methoxide (100 mL of a 0.5 M solution in methanol, 50.1 mmol) cooled to 0° C. was added a solution of 1-chloro-4,5-difluoro-2-nitro-benzene (9.7 g, 50.1 mmol) in methanol (10 mL) dropwise over 15 min. The solution was warmed to room temperature and stirred for 2 h, then poured slowly over ice. The yellow precipitate was collected by filtration and washed with cold water. The crystals were air dried to give 8.2 g (79%) of 1-chloro-4-fluoro-5-methoxy-2-nitro-benzene: Crude ¹H NMR (400 MHz, CDCl₃): δ 7.85 (d, J=10.5 Hz, 1H), 7.06 (d, J=7.3 Hz, 1H), 3.98 (s, 3H). The crude material was pure enough to carry on to the next step.

[0298] Part C

[0299] 1-Chloro-4-fluoro-5-methoxy-2-nitro-benzene (16.3 g, 79.3 mmol) and Sn granules (29.1 g, 246 mmol) were suspended in water (200 mL). Concentrated HCl (79 mL, 952 mmol) was added dropwise over 20 min. The resulting mixture was heated to 55° C. for 3 h. The solution was cooled to room temperature and carefully quenched with 1 N NaOH. The thick mixture was filtered through celite eluting the ethyl acetate to give a clear solution which was extracted with ethyl acetate. The ethyl acetate layers were washed with brine, dried (Na₂SO₄), filtered and concentrated in vacuo to give 26 g (80%) of 2-chloro-5-fluoro-4-methoxyaniline: Crude ¹H NMR (400 MHz, CDCl₃): δ 6.88 (d, J=8.3 Hz, 1H), 6.57 (d, J=12.2 Hz, 1H), 3.79 (s, 3H), 3.77 (br s, 2H). The crude material was pure enough to carry on to the next step.

[0300] Part D

[0301] 2-Chloro-5-fluoro-4-methoxyaniline (14.0 g, 79.7 mmol) was cooled to 0° C. and conc. HCl (40 mL) was added over 20 min. The suspension was heated to 55° C. until the aniline was completely dissolved, then cooled back to 0° C. A solution of sodium nitrite (6.1 g, 87.7 mmol) in water (15 mL) was added dropwise over 15 min. After complete addition the mixture was stirred at 0° C. for 30 min. Hexanes (24 mL) and dichloromethane (24 mL) were added followed by a solution of potassium iodide (26.5 g, 159.4 mmol) in water (25 mL) which was added dropwise over 30 min. After stirring at 0° C. for 4 h dichloromethane (50 mL) was added and the reaction quenched with sat. aq. NaHSO₃. The solution was extracted with dichloromethane. The organic layers were washed with brine, dried (Na₂SO₄), filtered and concentrated in vacuo to give 21 g (92%) of 1-chloro-4-fluoro-2-iodo-5-methoxy-benzene: Crude ¹H NMR (400 MHz, CDCl₃): δ 7.48 (d, J=10.3 Hz, 1H), 7.04 (d, J=7.8 Hz, 1H), 3.86 (s, 3H). The crude material was pure enough to carry on to the next step.

[0302] Part E

[0303] To 1-chloro-4-fluoro-2-iodo-5-methoxy-benzene (10.0 g, 34.9 mmol) in THF (70 mL) was cooled to −78° C. was added triisopropylborate (8.9 mL, 38.4 mmol) followed by dropwise addition of n-butyl lithium (24 mL of a 1.6 M solution in hexanes, 38.4 mL). The solution was stirred and allowed to warm to room temperature over night by dissipation of the dry ice/acetone bath. 1N HCl (50 mL0 and water (50 mL) were added and the solution stirred at room temperature for 1 h. The solution was extracted with ethyl acetate. The organic layers were washed with brine, dried (Na₂SO₄), filtered and concentrated in vacuo. The residue was triturated with 1:1 hexanes/diethyl ether and the solid collected by filtration to give 3.8 g (53%) of pure 1-chloro-4-fluoro-2-iodo-5-methoxyphenyl boronic acid: ¹H NMR (400 MHz, CDCl₃): δ 7.64 (d, J=11.7 Hz, 1H), 6.91 (d, J=7.3 Hz, 1H), 5.21 (br s, 2H), 3.90 (s, 3H).

PREPARATION 2 2-Chloro-4-dimethylamino-5-fluorophenylboronic acid

[0304] Parts A and B

[0305] A solution of 1-chloro-4,5-difluoro-2-nitro-benzene (Preparation 1) (20.0 g, 103.3 mmol), K₂CO₃ (31.4 g, 227.3 mmol) and dimethyl amine•HCl (9.3 g, 113.6 mmol) in acetonitrile (200 mL) was heated to reflux for 2 h. The solution cooled to room temperature, quenched with water and extracted with ethyl acetate. The ethyl acetate layers were washed with brine, dried (Na₂SO₄), filtered and concentrated in vacuo to give 22.1 g (98%) of 1-chloro-5-dimethylamino-4-fluoro-2-nitro-benzene: Crude ¹H NMR (400 MHz, CDCl₃): δ 7.83 (d, J=14.2 Hz, 1H), 6.72 (d, J=8.3 Hz, 1H), 3.09 (d, J=2.2 Hz, 6H), 3.77 (br s, 2H). The crude material was pure enough to carry on to the next step.

[0306] Parts C, D and E

[0307] 1-Chloro-4-fluoro-2-iodo-5-methoxyphenyl boronic acid was prepared substantially as described in Preparation 1, Parts C, D and E: ¹H NMR (400 MHz, CDCl₃): δ 7.52 (d, J=14.4 Hz, 1H), 6.71 (d, J=7.8 Hz, 1H), 5.18 (br s, 2H), 2.93 (d, J=1.2 Hz, 6H).

Example 1 (R,S)-8-(2,4-dichloro-phenyl)-4-isobutyl-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one

[0308] Parts A, B, and C

[0309] 2-Chloro-4-(2,4-dichloro-phenyl)-3-nitro-pyridine was prepared substantially as described in Example 9 and isolated as a brown viscous oil: crude ¹H NMR (300 MHz, CDCl₃): δ 8.6 (d, 1H), 7.5 (s, 1H), 7.38 (s, 1H), 7.34 (d, 1H), 7.20 (d, 1H).

[0310] Part D

[0311] 2-Chloro-4-(2,4-dichloro-phenyl)-3-nitro-pyridine (0.20 g, 0.66 mmol) and isobutylamine (0.096 g, 1.32 mmol) were treated substantially as described in Part D of Example 9 to yield 0.24 g (100%) of crude [4-(2.4-dichloro-phenyl)-2-nitro-pyridin-2-yl]-isobutyl-amine: MS (AP) m/z 340.2 [(M+H)⁺, 98].

[0312] Part E

[0313] [4-(2.4-Dichloro-phenyl)-2-nitro-pyridin-2-yl]-isobutyl-amine (0.24 g, 0.71 mmol) and Na₂S₂O4 (0.99 g, 5.69 mmol) were treated substantially as described in Part E of Example 9 to yield 0.22 g of 4-(2,4-dichloro-phenyl)-4-(2,4-dichloro-phenyl)-N²-isobutyl-pyridine-2,3-diamine: MS (AP) m/z 310.23 [(M+H)⁺, 78]. Taken on to Part F

[0314] Part F

[0315] 4-(2,4-Dichloro-phenyl)-4-(2,4-dichloro-phenyl)-N²-isobutyl-pyridine-2,3-diamine (0.22 g, 0.71 mmol) was treated substantially as described in Part F of Example 9 to give 6.7 mg (2.0%) of 8-(2,4-dichloro-phenyl)-4-isobutyl-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (Example 1): ¹H NMR (300 MHz, CD₃OD): □δ 8.6 (d, 1H), 7.6 (s, 1H), 7.45 (d, 1H), 7.39 (d, 1H), 7.25 (d, 1H), 4.4 (d, 2H), 2.4 (s, 2H), 2.35 (m, 1H), 1.25 (s, 1H), 0.95 (d, 6H). MS (ESI) m/z 362.3 [(M+H)⁺, 100].

Example 2 (R,S)-8-(2,4-dichloro-phenyl)-2-methyl-4-(1-methyl-butyl)-4H-pyrido[2,3-b]pyrazin-3-one

[0316] Parts A, B, and C

[0317] 2-Chloro-4-(2,4-dichloro-phenyl)-3-nitro-pyridine was prepared substantially as described in Example 9.

[0318] Part D

[0319] 2-Chloro-4-(2,4-dichloro-phenyl)-3-nitro-pyridine (0.20 g, 0.66 mmol) and 1-methyl-butylamine (0.11 g, 1.32 mmol) were treated substantially as described in Part D of Example 9 to produce 0.20 g (87%) of crude [4-(2,4-dichloro-phenyl)-3-nitro-pyridin-2-yl]-(1-methyl-butyl)-amine: MS (AP) m/z 354.2 [(M+H)+, 100].

[0320] Part E

[0321] [4-(2,4-Dichloro-phenyl)-3-nitro-pyridin-2-yl]-(1-methyl-butyl)-amine (0.25 g, 0.71 mmol) and Na₂S₂O₄ (1.00 g, 5.72 mmol) were treated substantially as described in Part E of Example 9 to yield 0.22 g (96%) of crude 4-(2,4-dichloro-phenyl)-N²-(1-methyl-butyl)-pyridine-2,3-diamine: MS (AP) m/z 324.3 [(M+H)+, 76].

[0322] Part F

[0323] 4-(2,4-Dichloro-phenyl)-N²-(1-methyl-butyl)-pyridine-2,3-diamine (0.22 g, 0.68 mmol) was treated substantially as described in Part F of Example 9 to give 3.5 mg (1.0%) of crude 8-(2,4-dichloro-phenyl)-2-methyl-4-(1-methyl-butyl)-4H-pyrido[2,3-b]pyrazin-3-one (Example 2): ¹H NMR (300 MHz, CD₃OD): δ 8.6 (d, 1H), 7.6 (s, 1H), 7.4 (d, 1H), 7.39 (d, 1H), 7.25 (d, 1H), 2.4 (s, 3H), 1.90 (m, 1H), 1.6 (s, 3H), 1.3 (s, 2H), 1.15 (m, 2H), 0.95 (t, 3H). MS (ESI) m/z 376.3 [(M+H)+, 100].

Example 3a (S)-4-(1-cyclopropyl-propyl)-8-(2,4-dichloro-phenyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one

[0324] Parts A, B, and C

[0325] 2-Chloro-4-(2,4-dichloro-phenyl)-3-nitro-pyridine was prepared substantially as described in Example 9.

[0326] Part D

[0327] 2-Chloro-4-(2,4-dichloro-phenyl)-3-nitro-pyridine (0.26 g, 0.86 mmol) and 1-cyclopropyl-propylamine (0.23 g, 1.71 mmol) were substantially as described in Part D of Example 9 to produce 2.32 g (100%) of crude (1-cyclopropyl-propyl)-[4-(2,4-dichloro-phenyl)-3-nitro-pyridin-2-yl]-amine: MS (AP) m/z 366.2 [(M+H)⁺, 96].

[0328] Part E

[0329] (1-Cyclopropyl-propyl)-[4-(2,4-dichloro-phenyl)-3-nitro-pyridin-2-yl]-amine (0.26 g, 0.71 mmol) and Na₂S₂O₄ (1.00 g, 5.72 mmol) were treated substantially as described in Part E of Example 9 to yield 1.60 g (75%) of crude N²-(1-cyclopropyl-propyl)-4-(2,4-dichloro-phenyl)-pyridine-2,3-diamine: MS (AP) m/z 336.3 [(M+H)⁺, 98].

[0330] Part F

[0331] N²-(1-cyclopropyl-propyl)-4-(2,4-dichloro-phenyl)-pyridine-2,3-diamine (0.16 g, 0.48 mmol) was treated substantially as described in Part F of Example 9 to give 8.3 mg (4.0%) of 4-(1-cyclopropyl-propyl)-8-(2,4-dichloro-phenyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (Example 3a): ¹H NMR (300 MHz, CD₃OD): δ 8.6 (d, 1H), 7.6 (s, 1H), 7.45 (d, 1H), 7.39 (d, 1H), 7.25 (d, 1H), 5.10 (m, 1H), 4.4 (m, 1H), 2.4 (s, 3H), 1.25 (s, 2H), 0.85 (t, 3H), 0.75 (m, 1H), 0.50-0.15 (m, 3H). MS (ESI) m/z 388.3 [(M+H)⁺, 100].

Example 3b (R)-4-(1-cyclopropyl-propyl)-8-(2,4-dichloro-phenyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one

[0332] Parts A, B, and C

[0333] 2-Chloro-4-(2,4-dichloro-phenyl)-3-nitro-pyridine was prepared substantially as described in Example 9.

[0334] Part D

[0335] 2-Chloro-4-(2,4-dichloro-phenyl)-3-nitro-pyridine (0.34 g, 1.12 mmol) and 1-cyclopropyl-propylamine (0.30 g, 2.24 mmol) were treated substantially as described in Part D of Example 9 to produce 0.26 g (83%) of crude (1-cyclopropyl-propyl)-[4-(2,4-dichloro-phenyl)-3-nitro-pyridin-2-yl]-amine: MS (AP) m/z 366.3 [(M+H)⁺, 100].

[0336] Part E

[0337] (1-Cyclopropyl-propyl)-[4-(2,4-dichloro-phenyl)-3-nitro-pyridin-2-yl]-amine (0.46 g, 1.26 mmol) and Na₂S₂O₄ (1.76 g, 10.1 mmol) were treated substantially as described in Part E of Example 9 to yield 0.16 g (66%) of crude N²-(1-cyclopropyl-propyl)-4-(2,4-dichloro-phenyl)-pyridine-2,3-diamine: MS (AP) m/z 336.3 [(M+H)⁺, 100].

[0338] Part F

[0339] N²-(1-cyclopropyl-propyl)-4-(2,4-dichloro-phenyl)-pyridine-2,3-diamine (0.25 g, 0.74 mmol) was treated substantially as described in Part F of Example 9 to give 6.1 mg (3%) of 4-(1-cyclopropyl-propyl)-8-(2,4-dichloro-phenyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (Example 3b) ¹H NMR (300 MHz, CD₃OD): δ 8.5 (d, 1H), 7.6 (s, 1H), 7.4 (d, 1H), 7.35 (d, 1H), 7.25 (d, 1H), 5.1 (q, 1H), 4.4 (q, 1H), 2.4 (s, 3H), 1.25 (s, 2H), 0.85 (t, 3H), 0.65 (m, 1H), 0.50-0.10 (m, 3H). MS (ESI) m/z 388.3 [(M+H)⁺, 100].

Example 4 (R,S)-8-(2,4-dichloro-phenyl)-4-(1,2-dimethyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one

[0340] Parts A, B, and C

[0341] 2-Chloro-4-(2,4-dichloro-phenyl)-3-nitro-pyridine was prepared substantially as described in Example 9.

[0342] Part D

[0343] 2-Chloro-4-(2,4-dichloro-phenyl)-3-nitro-pyridine (0.20 g, 0.66 mmol) and 1,2-dimethyl-propylamine (0.11 g, 1.32 mmol) were treated substantially as described in Part D of Example 9 to produce 0.26 g (100%) of [4-(2,4-dichloro-phenyl)-3-nitro-pyridin-2-yl]-(1,2-dimethyl-propyl)-amine. MS (AP) m/z 354.2 [(M+H)⁺, 100].

[0344] Part E

[0345] [4-(2,4-Dichloro-phenyl)-3-nitro-pyridin-2-yl]-(1,2-dimethyl-propyl)-amine (0.26 g, 0.74 mmol) and Na₂S₂O₄ (1.03 g, 5.94 mmol) were treated substantially as described in Part E of Example 9 to yield 0.18 g (75%) of crude 4-(2,4-dichloro-phenyl)-N²-(1,2-dimethyl-propyl)-pyridine-2,3-diamine: MS (AP) m/z 324.3 [(M+H)⁺, 70].

[0346] Part F

[0347] 4-(2,4-Dichloro-phenyl)-N²-(1,2-dimethyl-propyl)-pyridine-2,3-diamine (0.18 g, 0.56 mmol) was treated substantially as described in Part F of Example 9 to give 4.0 mg (2%) of 8-(2,4-dichloro-phenyl)-4-(1,2-dimethyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (Example 4): ¹H NMR (300 MHz, CD₃OD): δ 8.6 (d, 1H), 7.6 (s, 1H), 7.4 (d, 1H), 7.35 (d, 1H), 7.25 (d, 1H), 2.2 (s, 3H), 1.6 (m, 2H), 1.3 (s, 2H), 1.15 (d, 3H), 0.95 (m, 1H), 0.65 (bs, 3H). MS (ESI) m/z 376.3 [(M+H)⁺, 100].

Example 5 (R,S)-4-(1-cyclopropyl-butyl)-8-(2,4-dichloro-phenyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one

[0348] Part A

[0349] 2-Benzyloxy-4-chloro-3-nitro-pyridine (Wilde, et. al. WO 99/01454, which is incorporated herein by reference in its entirety) (11 g, 41.6 mmol) and 2,4-dichlorophenylboronic acid (11.9 g, 62.3 mmol) were treated substantially as described in Part A of Example 19a to give 8.0 g (51%) of 2-benzyloxy-4-(2,4-dichloro-phenyl)-3-nitro-pyridine: MS (AP) m/z 375.2 [(M+H)⁺, 100].

[0350] Part B

[0351] 2-Benzyloxy-4-(2,4-dichloro-phenyl)-3-nitro-pyridine (8.0 g, 21.3 mmol) was treated substantially as described in Part B of Example 19a to give 4-(2,4-dichloro-phenyl)-3-nitro-1H-pyridin-2-one (3.5 g, 58%): MS (AP) m/z 285.1 [(M+H)⁺, 98].

[0352] Part C

[0353] Trifluoro-methanesulfonic acid 4-(2,4-dichloro-phenyl)-3-nitro-pyridin-2-yl-ester (1.0 g, 2.40 mmol), prepared substantially as described in Part C of Example 19a, and 1-cyclopropyl-butylamine HCl (1.0 g, 4.79 mmol) were treated substantially as described in Part C of Example 19a to produce 0.66 g (72%) of crude (1-cyclopropyl-butyl)-[4-(2,4-dichloro-phenyl)-3-nitro-pyridin-2-yl]-amine: MS (AP) m/z 380.3 [(M+H)⁺, 100].

[0354] Part D

[0355] (1-Cyclopropyl-butyl)-[4-(2,4-dichloro-phenyl)-3-nitro-pyridin-2-yl]-amine (0.66 g, 1.74 mmol) and Na₂S₂O₄ (2.45 g, 14.0 mmol) were treated substantially as described in Part E of Example 9 to yield 0.44 g (72%) of N²-(1-cyclopropyl-butyl)-4-(2,4-dichloro-phenyl)-pyridine-2,3-diamine: MS (AP) m/z 350.3 [(M+H)⁺, 100].

[0356] Part E

[0357] N²-(1-Cyclopropyl-butyl)-4-(2,4-dichloro-phenyl)-pyridine-2,3-diamine (0.44 g, 1.26 mmol) was treated substantially as described in Part F of Example 9 to give 7.8 mg (2%) of 4-(1-cyclopropyl-butyl)-8-(2,4-dichloro-phenyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (Example 5): ¹H NMR (300 MHz, CDCl₃): δ 8.5 (d, 1H), 7.5 (s, 1H), 7.39 (d, 1H), 7.30 (s, 1H), 7.2 (d, 1H), 5.10 (q, 1H), 4.5 (q, 1H), 2.5 (s, 3H), 2.4-2.0 (m, 3H), 1.2 (m, 1H), 0.90 (t, 3H), 0.70 (m, 1H), 0.50-0.20 (m, 3H). MS (AP) m/z 402.33 [(M+H)+, 100].

Example 9 (R,S)-8-(2,4-dichloro-phenyl)-4-(2-methoxy-1-methyl-ethyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one

[0358] Part A

[0359] To a solution of 2-benzyloxy-4-chloro-3-nitro-pyridine (Wilde, et. al. WO 99/01454, which is incorporated herein by reference)(5 g, 18.9 mmol) in DME/H₂O, was added 2,4-dichlorophenylboronic acid (3.60 g, 18.9 mmol), Ba(OH)₂ 0.8H₂O (5.96 g, 18.9 mmol), and Pd(PPh₃)₂Cl₂ (0.77 g, 1.09 mmol) and the mixture was heated at reflux for 5 h. The reaction was cooled and poured into EtOAc and H₂O (500 mL). The EtOAc layer was washed with H₂O, brine, dried (Na₂SO₄), filtered and concentrated in vacuo. Purification using flash chromatography (10% EtOAc-Hexane) gave 5.79 g (82%) of 2-benzyloxy-4-(2,4-dichloro-phenyl)-3-nitro-pyridine as a viscous oil: crude MS (AP) m/z 375.2 [(M+H)⁺, 100].

[0360] Part B

[0361] 2-Benzyloxy-4-(2,4-dichloro-phenyl)-3-nitro-pyridine (5.79 g, 15.4 mmol) was dissolved in TFA (20 mL) and stirred at room temperature for 4 h. The reaction mixture was concentrated and washed with 20% EtOAc/Hexane, and concentrated in vacuo to yield 1.0 g (23%) of 4-(2,4-dichloro-phenyl)-3-nitro-1H-pyridin-2-one as a solid: crude MS (AP) m/z 285.1 [(M+H)⁺, 100].

[0362] Part C

[0363] To 10 mL of POCl₃ was added 4-(2,4-dichloro-phenyl)-3-nitro-1H-pyridin-2-one (1.0 g, 3.51 mmol), followed by the addition of DMF (1-2 mL) and the reaction refluxed for 5 h. The reaction mixture was cooled to room temperature and poured over ice-H₂O (200 mL). The solution was extracted with EtOAc, washed with H₂O, brine, dried (MgSO₄), filtered, and concentrated in vacuo to give 0.20 g (19%) of 2-chloro-4-(2,4-dichloro-phenyl)-3-nitro-pyridine as a brown viscous oil: crude ¹H NMR (300 MHz, CDCl₃): δ 8.6 (d, 1H), 7.5 (s, 1H), 7.38 (s, 1H), 7.34 (d, 1H), 7.20 (d, 1H).

[0364] Part D

[0365] 2-Chloro-4-(2,4-dichloro-phenyl)-3-nitro-pyridine (0.20 g, 0.66 mmol) was dissolved in acetonitrile (20 mL), followed by the addition of 2-methoxy-1-methyl-ethylamine (0.12 g, 1.32 mmol) and Hunig's base (0.037 g, 0.29 mmol). The reaction was stirred at reflux for 64 h. The solution was cooled to room temperature and extracted with EtOAc/H₂O. The organic layer was washed with brine, dried (Na₂SO₄), filtered, and concentrated to yield 0.20 g (87%) of [4-(2,4-dichloro-phenyl)-3-nitro-pyridin-2-yl]-(2-methoxy-1-methyl-ethyl)-amine: MS (AP) m/z 356.2 [(M+H)⁺, 86].

[0366] Part E

[0367] [4-(2,4-Dichloro-phenyl)-3-nitro-pyridin-2-yl]-(2-methoxy-1-methyl-ethyl)-amine (0.20 g, 0.56 mmol was dissolved in dioxane (8 mL) and H₂O (8 mL), followed by conc. NH₄OH (0.3 mL) and Na₂S₂O₄ (0.79 g, 4.53 mmol) and stirred at room temperature for 4 h. The solution was extracted with EtOAc, washed with H₂O, brine, dried (Na₂SO₄), filtered, and concentrated in vacuo to produce 0.13 g (72%) of 4-(2,4-dichloro-phenyl)-N²-(2-methoxy-1-methyl-ethyl)-pyridine-2,3-diamine: MS (AP) m/z 326.2 [(M+H)⁺, 90].

[0368] Part F

[0369] 4-(2,4-Dichloro-phenyl)-N²-(2-methoxy-1-methyl-ethyl)-pyridine-2,3-diamine (0.13 g, 0.40 mmol) was dissolved in toluene (20 mL), followed by methyl pyruvate (0.081 g, 0.80 mmol) and heated at reflux overnight. The reaction was concentrated in vacuo and purified by reverse phase prep HPLC to yield 3.2 mg (2%) of 8-(2,4-dichloro-phenyl)-4-(2-methoxy-1-methyl-ethyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (Example 9): ¹H NMR (300 MHz, CD₃OD): δ 8.6 (d, 1H), 7.6 (s, 1H), 7.4-7.25 (m, 3H), 4.4 (m, 1H). 3.8 (m, 1H), 3.3 (s, 3H), 2.4 (s, 3H), 1.6 (d, 2H), 1.25 (s, 2H). MS (AP) m/z 378.3 [(M+H)⁺, 100].

Example 10 (R,S)-8-(2,4-dichloro-phenyl)-4-(1-methoxymethyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one

[0370] Parts A, B, and C

[0371] 2-Chloro-4-(2,4-dichloro-phenyl)-3-nitro-pyridine was prepared substantially as described in Example 9.

[0372] Part D

[0373] 2-Chloro-4-(2,4-dichloro-phenyl)-3-nitro-pyridine (0.20 g, 0.66 mmol) and 1-methoxymethyl-propylamine (0.14 g, 1.32 mmol) were treated as in Part D of Example 9 to yield 0.21 g (88%) of [4-(2,4-dichloro-phenyl)-3-nitro-pyridin-2-yl]-(1-methoxymethyl-propyl)-amine: MS (AP) m/z 370.2 [(M+H)⁺, 97].

[0374] Part E

[0375] 4-(2,4-Dichloro-phenyl)-3-nitro-pyridin-2-yl]-(1-methoxymethyl-propyl)-amine (0.21 g, 0.57 mmol) and Na₂S₂O₄ (0.80 g, 4.58 mmol) were treated as in Part E of Example 9 to give 0.13 g (68%) crude 4-(2,4-dichloro-phenyl)-N²-(1-methoxymethyl-propyl)-pyridine-2,3-diamine: MS (AP) m/z 340.3 [(M+H)⁺, 100].

[0376] Part F

[0377] 4-(2,4-Dichloro-phenyl)-N²-(1-methoxymethyl-propyl)-pyridine-2,3-diamine (0.13 g, 0.38 mmol) was treated as in Part F of Example 9 to yield 3.0 mg (2%) of 8-(2,4-dichloro-phenyl)-4-(1-methoxymethyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (Example 10): ¹H NMR (300 MHz, CD₃OD): δ 8.6 (bs, 1H), 7.6 (s, 1H), 7.45-7.25 (m, 3H), 3.3 (s, 3H), 2.43 (s, 1H), 2.40 (s, 3H), 1.9 (m, 1H), 1.5 (m, 1H), 1.3 (s, 2H), 0.85 (t, 3H). MS (ESI) m/z 392.3 [(M+H)⁺, 100].

Example 10a (R)-8-(2,4-dichloro-phenyl)-4-(1-methoxymethyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one

[0378] Parts A and B

[0379] 4-(2,4-Dichloro-phenyl)-3-nitro-1H-pyridin-2-one was prepared substantially as described in Example 19a.

[0380] Part C

[0381] Trifluoro-methanesulfonic acid 4-(2,4-dichloro-phenyl)-3-nitro-pyridin-2-yl-ester (3.0 g, 7.19 mmol), prepared substantially as described in Part C of Example 19a, and 1-methoxymethyl-propylamine HCl (2.01 g, 14.4 mmol) were treated substantially as described in Part C of Example 19a to produce 2.11 g (79%) of [4-(2,4-dichloro-phenyl)-3-nitro-pyridin-2-yl]-(1-methoxymethyl-propyl)-amine: MS (AP) m/z 370.2 [(M+H)⁺, 100].

[0382] Part D

[0383] [4-(2,4-Dichloro-phenyl)-3-nitro-pyridin-2-yl]-(1-methoxymethyl-propyl)-amine (2.11 g, 5.72 mmol) and Na₂S₂O₄ (8.03 g, 46.1 mmol) were treated substantially as described in Part E of Example 9 to yield 1.14 g (59%) of 4-(2,4-dichloro-phenyl)-N²-(1-methoxymethyl-propyl)-pyridine-2,3-diamine: MS (AP) m/z 340.2 [(M+H)⁺, 100].

[0384] Part E

[0385] N²-(1-cyclopropyl-butyl)-4-(2,4-dichloro-phenyl)-pyridine-2,3-diamine (1.14 g, 3.35 mmol) was treated substantially as described in Part F of Example 9 to give 6.7 mg (0.5%) of (R)-8-(2,4-dichloro-phenyl)-4-(1-methoxymethyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (Example 10a): ¹H NMR (300 MHz, CDCl₃): δ 8.54 (bs, 1H), 7.54 (s, 1H), 7.40 (d, 1H), 7.28 (s, 1H), 7.20 (d, 1H), 6.2 (m, 1H), 4.3 (m, 1H), 3.8 (m, 1H), 3.3 (s, 3H), 2.47 (s, 3H), 2.0 (m, 1H), 1.30 (s, 1H), 0.90 (t, 3H). MS (AP) m/z 392.3 [(M+H)⁺, 100].

Example 10b (S)-8-(2,4-dichloro-phenyl)-2-methyl-4-(1-methoxymethyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one

[0386] Parts A, B, and C

[0387] 2-Chloro-4-(2,4-dichloro-phenyl)-3-nitro-pyridine was prepared substantially as described in Example 9.

[0388] Part D

[0389] 2-Chloro-4-(2,4-dichloro-phenyl)-3-nitro-pyridine (0.25 g, 0.82 mmol) and 1-methoxymethyl-propylamine (0.23 g, 1.65 mmol) were treated substantially as described in Part D of Example 9 to produce 0.25 g (83%) of [4-(2,4-dichloro-phenyl)-3-nitro-pyridin-2-yl]-(1-methoxymethyl-propyl)-amine: MS (AP) m/z 370.2 [(M+H)⁺, 98].

[0390] Part E

[0391] [4-(2,4-Dichloro-phenyl)-3-nitro-pyridin-2-yl]-(1-methoxymethyl-propyl)-amine (0.25 g, 0.67 mmol) and Na₂S₂O₄ (0.95 g, 5.45 mmol) were treated substantially as described in Part E of Example 9 to yield 0.13 g (56%) of 4-(2,4-dichloro-phenyl)-N²-(1-methoxymethyl-propyl)-pyridine-2,3-diamine: MS (AP) m/z 340.3 [(M+H)⁺, 100].

[0392] Part F

[0393] 4-(2,4-Dichloro-phenyl)-N²-(1-methoxymethyl-propyl)-pyridine-2,3-diamine (0.13 g, 0.38 mmol) was treated substantially as described in Part F of Example 9 to give 5.1 mg (3%) of (S)-8-(2,4-dichloro-phenyl)-2-methyl-4-(1-methoxymethyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (Example 10b): ¹H NMR (300 MHz, CD₃OD): δ 8.5 (d, 1H), 7.5 (s, 1H), 7.4 (d, 1H), 7.39 (d, 1H), 7.25 (d, 1H), 3.75 (m, 2H), 3.25 (s, 3H), 2.39 (s, 3H), 1.95 (m, 1H), 1.25 (s, 2H), 0.80 (t, 3H). MS (ESI) m/z 392.29 [(M+H)⁺, 100].

Example 18 (R,S)-8-(2-chloro-4-methoxy-phenyl)-2-methyl-4-(1-propyl-butyl)-4H-pyrido[2,3-b]pyrazin-3-one

[0394] Parts A and B

[0395] 4-(2,4-Dichloro-phenyl)-3-nitro-1H-pyridin-2-one was prepared substantially as described in Example 19a.

[0396] Part C

[0397] Trifluoro-methanesulfonic acid 4-(2-chloro-4-methoxy-phenyl)-3-nitro-pyridin-2-yl ester(0.50 g, 1.21 mmol), prepared substantially as described in Part C of Example 19a, and 1-propyl-butylamine (0.28 g, 2.42 mmol) were treated in the same manner as in Part C of Example 19a to produce 0.31 g (69%) of [4-(2-chloro-4-methoxy-phenyl)-3-nitro-pyridin-2-yl]-(1-propyl-butyl)-amine: MS (AP) m/z 377.9 [(M+H)⁺, 100].

[0398] Part D

[0399] [4-(2-Chloro-4-methoxy-phenyl)-3-nitro-pyridin-2-yl]-(1-propyl-butyl)-amine (0.31 g, 0.82 mmol) and Na₂S₂O₄ (1.15 g, 6.62 mmol) were treated substantially as described in Part E of Example 9 to give 0.49 g (100%) 4-(2-chloro-4-methoxy-phenyl)-N²-(1-propyl-butyl)-pyridine-2,3-diamine: MS (AP) m/z 347.9 [(M+H)⁺, 100].

[0400] Part E

[0401] 4-(2-Chloro-4-methoxy-phenyl)-N²-(1-propyl-butyl)-pyridine-2,3-diamine (0.49 g, 1.41 mmol) was treated substantially as described in Part F of Example 9 to give 1.3 mg (0.23%) of 8-(2-chloro-4-methoxy-phenyl)-2-methyl-4-(1-propyl-butyl)-4H-pyrido[2,3-b]pyrazin-3-one (Example 18): ¹H NMR (300 MHz, CDCl₃): δ 8.5 (d, 1H), 7.20 (d, 1H), 7.07 (s, 1H), 6.98 (d, 1H), 6.95 (d, 1H), 3.88 (s, 3H), 2.45 (s, 3H), 2.35-1.80 (m, 8H), 1.3-1.15 (m, 4H), 0.90 (t, 3H). MS (AP) m/z 399.9 [(M+H)⁺, 100].

Example 19a (S)-8-(2-chloro-4-methoxy-phenyl)-4-(1-cyclopropyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one

[0402] Part A

[0403] To a solution of 2-benzyloxy-4-chloro-3-nitro-pyridine (Wilde, et al. WO 99/01454, which is incorporated herein by reference) (3.0 g, 11.3 mmol) in ethanol (10 mL) and toluene (40 mL), was added Na₂CO₃ (14.17 mL, 2 M), 2-chloro-4-methoxyphenylboronic acid (3.17 g, 17.0 mmol), and Pd(PPh₃)₂Cl₂ (0.48 g, 0.68 mmol) and the mixture was heated at reflux for 5 h. The reaction was cooled and poured into EtOAc and H₂O (500 mL). The EtOAc layer was washed with H₂O, brine, dried (Na₂SO₄), filtered and concentrated in vacuo. Purification using flash chromatography (10% EtOAc-Hexane) gave 1.51 g (36%) of 2-benzyloxy-4-(2-chloro-4-methoxy-phenyl)-3-nitro-pyridine as a viscous oil: MS (AP) m/z 370.8 [(M+H)⁺, 100].

[0404] Part B

[0405] 2-Benzyloxy-4-(2-chloro-4-methoxy-phenyl)-3-nitro-pyridine (1.51 g, 4.07 mmol) was dissolved in TFA (20 mL) and stirred at room temperature for 4 h. The reaction mixture was concentrated, washed with toluene, and concentrated in vacuo to yield 1.19 g (100%) of 4-(2-chloro-4-methoxy-phenyl)-3-nitro-1H-pyridin-2-one as a solid: MS (AP) m/z 280.7 [(M+H)⁺, 100].

[0406] Part C

[0407] To a solution of 4-(2-chloro-4-methoxy-phenyl)-3-nitro-1H-pyridin-2-one (1.19 g, 4.24 mmol) in CH₂Cl₂ (50 mL), was added Na₂CO₃ (1.10 g, 10.4 mmol). The reaction was cooled to −78° C., and trifluoromethanesulfonic anhydride (3.55 g, 12.6 mmol) was added dropwise. After the addition, the reaction stirred for 15 min at −78° C., then warmed to 0° C. for 1 h to yield trifluoro-methanesulfonic acid 4-(2-chloro-4-methoxy-phenyl)-3-nitro-pyridin-2-yl ester. The reaction mixture was filtered and the collected solid was washed with CHCl₃. The filtrate was concentrated in vacuo and dissolved in toluene (20 mL), followed by Et₃N (0.20 mL, 1.45 mmol) and 1-cyclopropyl-propylamine HCl (0.16 g, 1.45 mmol), and heated at 130° C. overnight. The reaction was cooled and poured over an ice water bath. The mixture was extracted with CH₂Cl₂, washed with H₂O, brine, dried (MgSO₄), filtered, and concentrated in vacuo. Purification using flash chromatography (20% EtOAc/Hexane yielded 0.17 g (65%) of [4-(2-chloro-4-methoxy-phenyl)-3-nitro-pyridin-2-yl]-(1-cyclopropyl-propyl)-amine: MS (AP) m/z 361.8 [(M+H)⁺, 100].

[0408] Part D

[0409] [4-(2-Chloro-4-methoxy-phenyl)-3-nitro-pyridin-2-yl]-(1-cyclopropyl-propyl)-amine (0.17 g, 0.47 mmol) and Na₂S₂O₄ (0.66 g, 3.79 mmol) were treated substantially as described in Part E of Example 9 to give 0.14 g (88%) crude 4-(2-chloro-4-methoxy-phenyl)-N²-(1-cyclopropyl-propyl)-pyridine-2,3-diamine: MS (AP) m/z 331.8 [(M+H)⁺, 100].

[0410] Part E

[0411] 4-(2-Chloro-4-methoxy-phenyl)-N²-(1-cyclopropyl-propyl)-pyridine-2,3-diamine (0.14 g, 0.42 mmol) was treated substantially as described in Part F of Example 9 to give 4.2 mg (3%) of (R)-8-(2-chloro-4-methoxy-phenyl)-4-(1-cyclopropyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (Example 19a): ¹H NMR (300 MHz, CDCl₃): δ □8.5 (d, 1H), 7.30 (s, 1H), 7.20 (s, 1H), 7.07 (s, 1H), 6.9 (d, 1H), 5.0 (q, 1H), 4.45 (q, 1H), 3.88 (s, 3H), 2.5 (s, 3H), 2.4-2.0 (m, 3H), 0.90 (t, 3H), 0.75 (m, 1H), 0.50-0.25 (m, 2H). MS (AP) m/z 383.9 [(M+H)⁺, 100].

Example 19b (R)-8-(2-chloro-4-methoxy-phenyl)-4-(1-cyclopropyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one

[0412] Parts A and B

[0413] 4-(2-Chloro-4-methoxy-phenyl)-3-nitro-1H-pyridin-2-one was prepared substantially as described in Example 19a.

[0414] Part C

[0415] Trifluoro-methanesulfonic acid 4-(2-chloro-4-methoxy-phenyl)-3-nitro-pyridin-2-yl ester (0.91 g, 2.20 mmol), prepared substantially as described in Part C of Example 19a, and 1-cyclopropyl-propylamine HCl (0.56 g, 4.41 mmol) were treated substantially as described in Part C of Example 19a to produce 0.56 g (72%) of [4-(2-chloro-4-methoxy-phenyl)-3-nitro-pyridin-2-yl]-(1-cyclopropyl-propyl)-amine: MS (AP) m/z 361.8 [(M+H)⁺, 100].

[0416] Part D

[0417] [4-(2-Chloro-4-methoxy-phenyl)-3-nitro-pyridin-2-yl]-(1-cyclopropyl-propyl)-amine (0.56 g, 1.55 mmol) and Na₂S₂O₄ (2.17 g, 12.5 mmol) were treated substantially as described in Part E of Example 9 to give 0.49 g (96%) of crude 4-(2-chloro-4-methoxy-phenyl)-N²-(1-cyclopropyl-propyl)-pyridine-2,3-diamine: MS (AP) m/z 331.8 [(M+H)⁺, 100].

[0418] Part E

[0419] 4-(2-Chloro-4-methoxy-phenyl)-N²-(1-cyclopropyl-propyl)-pyridine-2,3-diamine (0.49 g, 1.48 mmol) was treated substantially as described in Part F of Example 9 to give 6.1 mg (1%) of 8-(2-chloro-4-methoxy-phenyl)-4-(1-cyclopropyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (Example 19b). ¹H NMR (300 MHz, CDCl₃): δ 8.43 (d, 1H), 7.29 (s, 1H), 7.20 (d, 1H), 7.07 (d, 1H), 6.94 (d, 1H), 5.0 (q, 1H), 4.5 (q, 2.5 (s, 3H), 2.3-2.0 (m, 3H), 0.90 (t, 3H), 0.85 (m, 1H), 0.50-0.30 (m, 2H). MS (AP) m/z 383.9 [(M+H)⁺, 100].

Example 23a 8-(2-chloro-4-methoxy-phenyl)-4-(1-cyclobutyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (Isomer A, R or S)

[0420] Parts A and B

[0421] 4-(2-Chloro-4-methoxy-phenyl)-3-nitro-1H-pyridin-2-one was prepared substantially as described in Example 19a.

[0422] Part C

[0423] Trifluoro-methanesulfonic acid 4-(2-chloro-4-methoxy-phenyl)-3-nitro-pyridin-2-yl ester (0.50 g, 1.21 mmol), prepared substantially as described in Part C of Example 19a, and 1-cyclobutyl-propylamine HCl (0.36 g, 2.42 mmol) were treated substantially as described in Part C of Example 19a to produce 0.33 g (73%) of [4-(2-chloro-4-methoxy-phenyl)-3-nitro-pyridin-2-yl]-(1-cyclobutyl-propyl)-amine: MS (AP) m/z 375.9 [(M+H)⁺, 100].

[0424] Part D

[0425] [4-(2-Chloro-4-methoxy-phenyl)-3-nitro-pyridin-2-yl]-(1-cyclobutyl-propyl)-amine (0.33 g, 0.88 mmol) and Na₂S₂O₄ (1.33 g, 7.6 mmol) were treated substantially as described in Part E of Example 9 to give 0.33 g (100%) 4-(2-chloro-4-methoxy-phenyl)-N²-(1-cyclobutyl-propyl)-pyridine-2,3-diamine: MS (AP) m/z 345.9 [(M+H)⁺, 100].

[0426] Part E

[0427] 4-(2-Chloro-4-methoxy-phenyl)-N²-(1-cyclobutyl-propyl)-pyridine-2,3-diamine (0.33 g, 9.53 mmol) was treated substantially as described in Part F of Example 9 to give 1.3 mg (0.34%) of 8-(2-chloro-4-methoxy-phenyl)-4-(1-cyclobutyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (Example 23a): ¹H NMR (300 MHz, CDCl₃): δ 8.5 (d, 1H), 7.22 (d, 1H), 7.20 (d, 1H), 7.06 (s, 1H), 6.90 (d, 1H), 5.9 (m, 1H), 3.88 (s, 3H), 2.45 (s, 3H), 2.2 (m, 1H), 1.9-1.6 (m, 8H), 0.75 (t, 3H). MS (AP) m/z 397.9 [(M+H)⁺, 100].

Example 23b 8-(2-chloro-4-methoxy-phenyl)-4-(1-cyclobutyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (Isomer B, R or S)

[0428] Parts A and B

[0429] 4-(2-Chloro-4-methoxy-phenyl)-3-nitro-1H-pyridin-2-one was prepared substantially as described in Example 19a.

[0430] Part C

[0431] Trifluoro-methanesulfonic acid 4-(2-chloro-4-methoxy-phenyl)-3-nitro-pyridin-2-yl ester (0.50 g, 1.21 mmol), prepared substantially as described in Example 19a, and 1-cyclobutyl-propylamine HCl (0.36 g, 2.42 mmol) were treated substantially as described in Part C of Example 19a to produce 0.33 g (72%) of [4-(2-chloro-4-methoxy-phenyl)-3-nitro-pyridin-2-yl]-(1-cyclobutyl-propyl)-amine: MS (AP) m/z 375.9 [(M+H)⁺, 25].

[0432] Part D

[0433] [4-(2-Chloro-4-methoxy-phenyl)-3-nitro-pyridin-2-yl]-(1-cyclobutyl-propyl)-amine (0.33 g, 0.88 mmol) and Na₂S₂O₄ (1.33 g, 7.6 mmol) were treated substantially as described in Part E of Example 9 to give 0.46 g (100%) 4-(2-chloro-4-methoxy-phenyl)-N²-(1-cyclobutyl-propyl)-pyridine-2,3-diamine: MS (AP) m/z 345.9 [(M+H)⁺, 100].

[0434] Part E

[0435] 4-(2-chloro-4-methoxy-phenyl)-N²-(1-cyclobutyl-propyl)-pyridine-2,3-diamine (0.46 g, 1.33 mmol) was treated substantially as described in Part F of Example 9 to give 0.7 mg (0.13%) of 8-(2-chloro-4-methoxy-phenyl)-4-(1-cyclobutyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (Example 23b): ¹H NMR (300 MHz, CDCl₃): δ 8.5 (d, 1H), 7.22 (d, 1H), 7.20 (d, 1H), 7.07 (s, 1H), 6.9 (d, 1H), 5.9 (m, 111), 3.88 (s, 3H), 2.5 (s, 3H), 2.3-1.8 (m, 9H), 0.80 (t, 3H). MS (AP) m/z 397.9 [(M+H)⁺, 100].

Example 25a (S)-8-(2-chloro-4-methoxy-phenyl)-4-(2-methoxy-1-methyl-ethyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one

[0436] Parts A and B

[0437] 4-(2-Chloro-4-methoxy-phenyl)-3-nitro-1H-pyridin-2-one was prepared substantially as described in Example 19a.

[0438] Part C

[0439] Trifluoro-methanesulfonic acid 4-(2-chloro-4-methoxy-phenyl)-3-nitro-pyridin-2-yl ester (0.48 g, 1.16 mmol), prepared substantially as described in Part C of Example 19a, and 2-methoxy-1-methyl-ethylamine (0.21 g, 2.32 mmol) were treated substantially as described in Part C of Example 19a to produce 0.28 g (68%) of [4-(2-chloro-4-methoxy-phenyl)-3-nitro-pyridin-2-yl]-(2-methoxy-1-methyl-ethyl)-amine: MS (AP) m/z 351.8 [(M+H)⁺, 90].

[0440] Part D

[0441] [4-(2-chloro-4-methoxy-phenyl)-3-nitro-pyridin-2-yl]-(2-methoxy-1-methyl-ethyl)-amine (0.28 g, 0.80 mmol) and Na₂S₂O₄ (1.12 g, 6.42 mmol) were treated substantially as described in Part E of Example 9 to give 0.22 g (84%) 4-(2-chloro-4-methoxy-phenyl)-N²-(2-methoxy-1-methyl-ethyl)-pyridine-2,3-diamine: MS (AP) m/z 321.8 [(M+H)⁺, 72].

[0442] Part E

[0443] 4-(2-chloro-4-methoxy-phenyl)-N²-(2-methoxy-1-methyl-ethyl)-pyridine-2,3-diamine (0.22 g, 0.68 mmol) was treated substantially as described in Part F of Example 9 to give 6.8 mg (3%) of 8-(2-chloro-4-methoxy-phenyl)-4-(2-methoxy-1-methyl-ethyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (Example 25a): ¹H NMR (300 MHz, CDCl₃): δ 8.50 (d, 1H), 7.23 (d, 1H), 7.21 (d, 1H), 7.07 (s, 1H), 6.93 (d, 1H), 4.4 (t, 1H), 3.87 (s, 3H), 3.80 (q, 1H), 3.34 (s, 3H), 2.48 (s, 3H), 1.62 (d, 3H) 1.25 (s, 1H). MS (AP) m/z 373.8 [(M+H)⁺, 100].

Example 25b (R)-8-(2-chloro-4-methoxy-phenyl)-4-(2-methoxy-1-methyl-ethyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one

[0444] Parts A and B

[0445] 4-(2-Chloro-4-methoxy-phenyl)-3-nitro-1H-pyridin-2-one was prepared substantially as described in Example 19a.

[0446] Part C

[0447] Trifluoro-methanesulfonic acid 4-(2-chloro-4-methoxy-phenyl)-3-nitro-pyridin-2-yl ester (1.0 g, 2.42 mmol), prepared substantially as described in Part C of Example 19a, and 2-methoxy-1-methyl-ethylamine HCl (0.61 g, 4.85 mmol) were treated substantially as described in Part C of Example 19a to produce 0.29 g (34%) of [4-(2-chloro-4-methoxy-phenyl)-3-nitro-pyridin-2-yl]-(2-methoxy-1-methyl-ethyl)-amine: MS (AP) m/z 351.8 [(M+H)⁺, 100].

[0448] Part D

[0449] [4-(2-Chloro-4-methoxy-phenyl)-3-nitro-pyridin-2-yl]-(2-methoxy-1-methyl-ethyl)-amine (0.10 g, 0.27 mmol) and Na₂S₂O₄ (0.38 g, 2.21 mmol) were treated substantially as described in Part E of Example 9 to give 0.21 g (81%) 4-(2-chloro-4-methoxy-phenyl)-N²-(2-methoxy-1-methyl-ethyl)-pyridine-2,3-diamine: MS (AP) m/z 321.8 [(M+H)⁺, 100].

[0450] Part E

[0451] 4-(2-Chloro-4-methoxy-phenyl)-N²-(2-methoxy-1-methyl-ethyl)-pyridine-2,3-diamine (0.21 g, 0.65 mmol) was treated substantially as described in Part F of Example 9 to give 7.3 mg (3%) of (R)-8-(2-chloro-4-methoxy-phenyl)-4-(2-methoxy-1-methyl-ethyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (Example 25b): ¹H NMR (300 MHz, CDCl₃): δ 8.51 (d, 1H), 7.26 (d, 1H), 7.21 (s, 1H), 7.07 (s, 1H), 6.93 (d, 1H),4.4 (t, 1H), 3.87 (s, 3H), 3.80 (m, 2H), 3.3 (s, 3H), 2.50 (s, 3H), 1.60 (d, 3H). MS (AP) m/z 373.8 [(M+H)⁺, 100].

Example 26a (S)-8-(2-chloro-4-methoxy-phenyl)-4-(1-methoxymethyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one

[0452] Parts A and B

[0453] 4-(2-Chloro-4-methoxy-phenyl)-3-nitro-1H-pyridin-2-one was prepared substantially as described in Example 19a.

[0454] Part C

[0455] Trifluoro-methanesulfonic acid 4-(2-chloro-4-methoxy-phenyl)-3-nitro-pyridin-2-yl ester (0.40 g, 0.97 mmol), prepared substantially as described in Part C of Example 19a, and 1-methoxymethyl-propylamine HCl (0.27 g, 1.94 mmol) were treated substantially as described in Part C of Example 19a to produce 0.10 g (28%) of [4-(2-chloro-4-methoxy-phenyl)-3-nitro-pyridin-2-yl]-(1-methoxymethyl-propyl)-amine: MS (AP) m/z 365.8 [(M+H)⁺, 100].

[0456] Part D

[0457] [4-(2-Chloro-4-methoxy-phenyl)-3-nitro-pyridin-2-yl]-(1-methoxymethyl-propyl)-amine (0.10 g, 0.27 mmol) and Na₂S₂O₄ (0.38 g, 2.21 mmol) were treated substantially as described in Part E of Example 9 to give 0.08 g (87%) 4-(2-chloro-4-methoxy-phenyl)-N²-(1-methoxymethyl-propyl)-pyridine-2,3-diamine: MS (AP) m/z 335.8 [(M+H)⁺, 100].

[0458] Part E

[0459] 4-(2-Chloro-4-methoxy-phenyl)-N²-(1-methoxymethyl-propyl)-pyridine-2,3-diamine (0.080 g, 0.24 mmol) was treated substantially as described in Part F of Example 9 to give 2.7 mg (3%) of 8-(2-chloro-4-methoxy-phenyl)-4-(1-methoxymethyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (Example 26a): ¹H NMR (300 MHz, CDCl₃): δ 8.50 (bs, 1H), 7.28 (s, 1H), 7.22 (d, 1H), 7.07 (s, 1H), 6.91 (d, 1H), 3.88 (s, 3H), 3.84 (m, 1H), 3.38 (s, 3H), 2.50 (s, 3H), 1.25 (s, 1H), 0.90 (t, 3H), 0.10 (s, 3H). MS (AP) m/z 387.9 [(M+H)⁺, 100].

Example 67a (R)-4-(1-cylcopropropyl-propyl)-8-(4-methoxy-2-methyl-phenyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one

[0460] Part A

[0461] To a solution of 2-benzyloxy-4-chloro-3-nitro-pyridine (Wilde, et al. WO 99/01454, which is incorporated herein by reference) (0.98 g, 3.7 mmol) in ethanol (10 mL) and toluene (40 mL), was added Na₂CO₃ (4.6 mL, 2M), 4-methoxy-2-methylphenyl boronic acid (1.0 g, 5.6 mmol), and Pd(PPh₃)₂Cl₂ (0.156 g, 0.22 mmol) and the mixture was heated at reflux for 5 h. The reaction was cooled and poured into EtOAc and H₂O (500 mL). The EtOAc layer was washed with H₂O, brine, dried Na₂SO₄, filtered and concentrated in vacuo. Purification using flash chromatography (10% EtOAc/hexane) gave 1.01 g (78%) of 2-benzyloxy-4-(4-methoxy-2-methyl-phenyl)-3-nitro-2,3-dihydro-pyridine as a viscous oil; MS(AP) m/z 351.6 [(M+H)⁺, 100], 392.0 [(M+H+CH₃CN)⁺, 35]. The purified intermediate was used in the following step.

[0462] Part B

[0463] 2-Benzyloxy-4-(4-methoxy-2-methyl-phenyl)-3-nitro-2,3-dihydro-pyridine (1.01 g, 2.9 mmol) was dissolved in TFA (25 mL) and stirred at room temperature for 4 h. The reaction mixture was concentrated in vacuo and the crude product 4-(4-methoxy-2-methyl-phenyl)-3-nitro-3H-pyridin-2-one: MS(AP) m/z 261.0 [(M+H)⁺, 87]. The crude intermediate was used in the next step.

[0464] Part C

[0465] To a solution of 4-(4-methoxy-2-methyl-phenyl)-3-nitro-3H-pyridin-2-one (0.321 g, 1.23 mmol) CH₂Cl₂ (13 mL), was added Na₂CO₃ (0.317 g, 3.02 mmol). The reaction was cooled to −78° C., and trifluoromethanesulfonic anhydride (617 μL, 3.65 mmol) was added dropwise. After the addition, the reaction stirred for 15 min at −78° C., then warmed to 0° C. for 1 h. The reaction mixture was filtered and the collected solid was washed with CHCl₃. The filtrate was concentrated in vacuo and dissolved in toluene (20 mL) followed by Et₃N (343 μL, 2.4 mmol) and 1-cyclopropyl propyl amine HCl (0.331 g, 2.4 mmol), and heated at 130° C. overnight. The reaction was cooled and poured onto ice/H₂O. The mixture was extracted with CH₂Cl₂, washed with H₂O, brine, dried Na₂SO₄, filtered, and concentrated in vacuo. Purification using flash chromatography (10% EtOAc/Hexane) gave 0.220 g (54%) of (1-cyclopropyl-propyl)-[4-(4-methoxy-2-methyl-phenyl)-3-nitro-pyridin-2-yl]-amine: MS(AP) m/z 342.1 [(M+H)⁺, 100]. The purified intermediate was used in the following step.

[0466] Part D

[0467] (1-Cyclopropyl-propyl)-[4-(4-methoxy-2-methyl-phenyl)-3-nitro-pyridin-2-yl]-amine (0.220, 0.64 mmol) was dissolved in dioxane (10 mL) and H₂O (10 mL), followed by conc. NH₄OH (0.4 mL) and Na₂S₂O₄ (0.906 g, 5.2 mmol) and stirred at room temperature for 4 h. The solution was extracted with EtOAc, washed with H₂O, brine, dried Na₂SO₄, filtered, and concentrated in vacuo to produce the crude intermediate N²-(1-cyclopropyl-propyl)-4-(4-methoxy-2-methyl-phenyl)-pyridine-2,3-diamine; MS(AP) m/z 312.2 [(M+H)⁺, 100]. The crude intermediate was used in the following step.

[0468] Part E

[0469] N²-(1-cyclopropyl-propyl)-4-(4-methoxy-2-methyl-phenyl)-pyridine-2,3-diamine (0.183 g, 0.59 mmol) was dissolved in toluene (10 mL), followed by methyl pyruvate (106 μL, 1.2 mmol) and heated to 130° C. overnight. The reaction was concentrated in vacuo and purified by reverse phase reverse phase prep HPLC to yield 4-(1-cylcopropropyl-propyl)-8-(4-methoxy-2-methyl-phenyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (Example 67a): ¹H NMR (300 MHz, CDCl₃): δ 8.48-8.41 (2d, 1H, J=4.7 Hz), 7.26-7.10 (m, 2H), (m, 2H), 6.87-6.83 (m, 2H), 5.09-5.02, 4.53-4.43 (2m, 1H), 3.87 (s, 3H), 2.49 (s, 3H), 2.42-2.38 (m,1H), 2.12 (s, 3H), 2.09-2.02 (m, 1H), 0.90-0.87 (t, 3H, J=5.1 Hz), 0.80-0.77 (m, 1H), 0.59-0.55 (m, 1H), 0.41-0.29 (m, 1H), 0.26-0.22 (m, 1H). MS (AP) 364.1 [(M+H)⁺, 100].

Example 69 (R,S)-4-(1-cyclopropyl-butyl)-8-(4-methoxy-2-methyl-phenyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one

[0470] Part A-B

[0471] 4-(4-Methoxy-2-methyl-phenyl)-3-nitro-3H-pyridin-2-one was prepared as substantially described in Example 67a.

[0472] Part C

[0473] Trifluoro-methanesulfonic acid 4-(4-methoxy-2-methyl-phenyl)-3-nitro-pyridin-2-yl-ester (0.764 g, 1.95 mmol), prepared substantially as described in Part C of Example 67a, and 1-cylcopropyl-butyl amine HCl (0.580 g, 3.9 mmol) were treated substantially as described in Part C of Example 67a to produce 0.230 g (50%) of (1-cyclopropyl-butyl)-[4-(4-methoxy-2-methyl-phenyl)-3-nitro-pyridin-2-yl]amine.

[0474] Part D

[0475] (1-Cyclopropyl-butyl)-[4-methoxy-2-methyl-phenyl)-3-nitro-pyridin-2-yl]amine (0.230 g, 0.65 mmol), and Na₂SO₄ (0.910 g, 5.2 mmol), were treated substantially as described in Part D of Example 67a to give a crude yield of 0.226 g (107%) of N²-(1-cyclopropyl-butyl)-4-(4-methoxy-2-methyl-phenyl)-pyridine-2,3-diamine: MS(AP) m/z 326.3 [(M+H)⁺, 94].

[0476] Part E

[0477] N²-(1-cylcopropyl-butyl)-4-(4-methoxy-2-methyl-phenyl)-pyridine-2,3-diamine (0.226 g, 0.69 mmol) and methyl pyruvate (126 μL, 1.4 mmol) were treated substantially as described in Part E of Example 67a to give 4-(1-cyclopropyl-butyl)-8-(4-methoxy-2-methyl-phenyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (Example 69): ¹H NMR (300 MHz, CDCl₃): δ 8.47-8.39 (2d, 1H, J=4.7 Hz), 7.23-7.08 (m, 2H), 6.85-6.80 (m, 2H), 5.17-5.09, 4.57-4.49 (2m, 1H), 3.84 (s, 3H), 2.47 (s,3H), 2.4-2.2 (m, 3H), 2.16 (s, 3H), 1.98-1.94 (m, 2H), 0.89-0.84 (t, 3H, J=7.4 Hz), 0.69-0.67 (m, 1H), 0.53-0.49 (m, 1H), 0.46-0.43 (m, 1H), 0.22-0.19 (m, 1H). MS (AP) 378.1 [(M+H)⁺, 100].

Example 73a (R)-4-(2-methoxy-1-methyl-ethyl)-8-(4-methoxy-2-methyl-phenyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one

[0478] Part A-B

[0479] 4-(4-Methoxy-2-methyl-phenyl)-3-nitro-3H-pyridin-2-one was prepared substantially as described in Example 67a.

[0480] Part C

[0481] Trifluoro-methanesulfonic acid 4-(4-methoxy-2-methyl-phenyl)-3-nitro-pyridin-2-yl-ester (0.332 g, 0.74 mmol), prepared substantially as described in Part C of Example 67a, and 2-methoxy-1-methyl-ethylamine HCl (0.263 g, 67 mmol) were treated substantially as described in Part C of Example 67a to produce 0.120 g (54%) of (2-methoxy-1-methyl-ethyl)-[4-(4-methoxy-2-methyl-phenyl)-3-nitro-pyridin-2-yl]amine; MS(AP) m/z 332.1 [(M+H)⁺, 94].

[0482] Part D

[0483] 2-Methoxy-1-methyl-ethyl)-[4-(4-methoxy-2-methyl-phenyl)-3-nitro-pyridin-2-yl]amine (0.120 g, 0.36 mmol), and Na₂SO₄ (0.509 g, 2.9 mmol), were treated as in Part D of Example 67a to give a crude yield of 0.066 g (61%) of N²-(2-methoxy-1-methyl-ethyl)-4-(4-methoxy-2-methyl-phenyl)-pyridine-2,3-diamine; MS(AP) m/z 302.2 [(M+H)⁺, 100]. The crude product was taken on to Part E.

[0484] Part E

[0485] N²-(2-Methoxy-1-methyl-ethyl)-4-(4-methoxy-2-methyl-phenyl)-pyridine-2,3-diamine (0.066 g, 0.22 mmol) and methyl pyruvate (79 μL, 0.88 mmol) were treated substantially as in Part E of Example 67a to give 4-(2-methoxy-1-methyl-ethyl)-8-(4-methoxy-2-methyl-phenyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (Example 73a): ¹H NMR (300 MHz, CDCl₃): δ 8.49-8.47 (d, 1H, J=4.8 Hz), 7.16-7.12 (m, 2H), 6.86-6.82 (m, 2H), 4.41-4.36 (m, 1H), 3.87 (s, 3H), 3.84-3.80 (m, 2H), 3.34 (s, 3H), 2.48 (s, 3H), 2.12 (s, 3H), 1.62-1.60 (d, 3H, J=6.9 Hz). MS (AP) 354.2 [(M+H)⁺, 100].

Example 74a (R,S)-8-(4-Methoxy-2-methyl-phenyl)-4-(1-methoxymethyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one

[0486] Part A-B

[0487] 4-(4-Methoxy-2-methyl-phenyl)-3-nitro-3H-pyridin-2-one was prepared substantially as described in Example 67a.

[0488] Part C

[0489] Trifluoro-methanesulfonic acid 4-(4-methoxy-2-methyl-phenyl)-3-nitro-pyridin-2-yl-ester (0.78 g, 1.98 mmol), prepared substantially as described in Part C of Example 67a, and 1-methoxymethyl-propylamine (0.45 g, 4.36 mmol) were treated substantially as described in Part C of Example 67a to produce 27 mg (40%) of [4-(4-methoxy-2-methyl-phenyl)-3-nitro-pyridin-2-yl]-(1-methoxymethyl-propyl)-amine; MS (EI) m/z 346.33 [(M+H)⁺, 100].

[0490] Part D

[0491] [4-(4-Methoxy-2-methyl-phenyl)-3-nitro-pyridin-2-yl]-(1-methoxymethyl-propyl)-amine (0.43 g, 0.36 mmol) and SnCl₂ (0.2 g, 1.08 mmol) in ethanol (2 mL) were heated to 70° C. for 4 h. The solution was cooled to room temperature and quenched with saturated aqueous NaHCO₃ then extracted with EtOAc, washed with H₂O, brine, dried (Na₂SO₄), filtered, and concentrated in vacuo to give a crude yield of 0.40 g (99%) of 4-(4-methoxy-2-methyl-phenyl)-N²-(1-methoxymethyl-propyl)-pyridine-2,3-diamine; MS(EI) m/z 316.28 [(M+H)⁺, 100]. The crude product was taken on to Part E.

[0492] Part E

[0493] 4-(4-Methoxy-2-methyl-phenyl)-N²-(1-methoxymethyl-propyl)-pyridine-2,3-diamine (0.08 g, 0.25 mmol) and methyl pyruvate (33 μL, 0.38 mmol) were treated substantially as in Part E of Example 67a to give 3.0 mg of 8-(4-methoxy-2-methyl-phenyl)-4-(1-methoxymethyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (Example 74a): ¹H NMR (400 MHz, CDCl₃) δ ppm 8.46 (d, J=4.89 Hz, 1 H), 7.15 (d, J=8.31 Hz, 1 H), 7.12 (d, J=4.40 Hz, 1 H), 6.85 (d, J=6.60 Hz, 1 H), 6.83 (d, J=12.23 Hz, 1 H), 5.89 (m, 1 H), 4.38 (m, 1 H), 3.86 (s, 3 H), 3.77 (m, 1 H), 3.32 (s, 3 H), 2.46 (s, 3 H), 2.11 (s, 3 H), 1.77 (m, 2 H), 0.86 (t, J=7.34 Hz, 2 H). MS (EI) 368.30 [(M+H)⁺, 100]

Example 83a (R)-4-(1-Cyclopropyl-propyl)-8-(5-fluoro-4-methoxy-2-methyl-phenyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one

[0494] Part A and B

[0495] 4-(5-Fluoro-4-methoxy-2-methyl-phenyl)-3-nitro-1H-pyridin-2-one was prepared substantially as described in Example 90a.

[0496] Part C

[0497] Trifluoro-methanesulfonic acid 4-(5-fluoro-4-methoxy-2-methyl-phenyl)-3-nitro-pyridin-2-yl ester (0.5 g, 1.22 mmol), prepared substantially as described in Part C of Example 19a, and (R)-1-cyclopropyl-propylamine (0.33 g, 2.44 mmol) were treated substantially as described in Part C of Example 19a to produce 0.17 g (43%) of crude (R)-(1-Cyclopropyl-propyl)-[4-(5-fluoro-4-methoxy-2-methyl-phenyl)-3-nitro-pyridin-2-yl]-amine.

[0498] Part D

[0499] (R)-(1-Cyclopropyl-propyl)-[4-(5-fluoro-4-methoxy-2-methyl-phenyl)-3-nitro-pyridin-2-yl]-amine (0.17 g, 0.47 mmol) and Na₂S₂O₄ (1.24 g, 7.10 mmol) were treated as in Part E of Example 9 to give 0.15 g (98%) crude (R)-N²-(1-Cyclopropyl-propyl)-4-(5-fluoro-4-methoxy-2-methyl-phenyl)-pyridine-2,3-diamine.

[0500] Part E

[0501] (R)-N²-(1-Cyclopropyl-propyl)-4-(5-fluoro-4-methoxy-2-methyl-phenyl)-pyridine-2,3-diamine (0.15 g, 0.46 mmol) was treated substantially as described in Part F of Example 9 to give 4.5 mg (3%) of (R)-4-(1-Cyclopropyl-propyl)-8-(5-fluoro-4-methoxy-2-methyl-phenyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (Example 83a). ¹H NMR (300 MHz, CDCl₃) δ ppm 8.36 (d, J=4.76 Hz, 1 H), 7.03 (d, J=4.76 Hz, 1 H), 6.93 (d, J=11.72 Hz, 1 H), 6.83 (d, J=8.42 Hz, 1 H), 4.95 (m, 1 H), 3.89 (s, 3 H), 2.43 (s, 3 H), 2.20 (m, 2 H), 2.03 (s, 3 H), 0.80 (t, J=7.51 Hz, 3 H), 0.53 (m, 2 H), 0.26 (m, 2 H), 0.10 (m, 1 H). MS (EI) m/z 382.3 [(M+H)+, 100].

Example 90a (R)-8-(5-Fluoro-4-methoxy-2-methyl-phenyl)-4-(1-methoxymethyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one

[0502] Part A

[0503] 2-Benzyloxy-4-chloro-3-nitro-pyridine (Wilde, et. al. WO 99/01454) (1.0 g, 3.78 mmol) and 5-fluoro-4-methoxy-2-methyl-phenylboronic acid (prepared substantially as described in Speicher, A.; Kolz, J.; Sambanje, R. P. Synthesis, 2002, 17, 2503, which is incorporated herein by reference) (1.2 mg, 5.67 mmol) were treated substantially as described in Part A of Example 19a to give 1.15 g (83%) of 2-benzyloxy-4-(5-fluoro-4-methoxy-2-methyl-phenyl)-3-nitro-pyridine: MS (EI) m/z 369.3 [(M+H)⁺, 100].

[0504] Part B

[0505] 2-Benzyloxy-4-(5-fluoro-4-methoxy-2-methyl-phenyl)-3-nitro-pyridine (1.5 g, 4.1 mmol) was treated substantially as described in Part B of Example 19a to give 4-(2-chloro-4-methoxy-5-methyl-phenyl)-3-nitro-1H-pyridin-2-one (1.1 g, 92%): MS (EI) m/z 279.1 [(M+H)⁺, 100].

[0506] Part C

[0507] Trifluoro-methanesulfonic acid 4-(5-fluoro-4-methoxy-2-methyl-phenyl)-3-nitro-pyridin-2-yl ester (0.5 g, 1.2 mmol), prepared substantially as described in Part C of Example 19a, and (R)-1-methoxymethyl-propylamine.HCl (0.34 g, 2.4 mmol) were treated substantially as described in Part C of Example 19a to produce 0.16 g (37%) of crude (R)-[4-(5-fluoro-4-methoxy-2-methyl-phenyl)-3-nitro-pyridin-2-yl]-(1-methoxymethyl-propyl)-amine.

[0508] Part D

[0509] (R)-[4-(5-fluoro-4-methoxy-2-methyl-phenyl)-3-nitro-pyridin-2-yl]-(1-methoxymethyl-propyl)-amine (0.16 g, 0.44 mmol) and Na₂S₂O₄ (1.15 g, 6.6 mmol) were treated as in Part E of Example 9 to give 0.15 g (98%) crude (R)-4-(5-Fluoro-4-methoxy-2-methyl-phenyl)-N²-(1-methoxymethyl-propyl)-pyridine-2,3-diamine. MS (AP) m/z 334.3 [(M+H)⁺, 100].

[0510] Part E

[0511] (R)-4-(5-Fluoro-4-methoxy-2-methyl-phenyl)-N²-(1-methoxymethyl-propyl)-pyridine-2,3-diamine (0.15 g, 0.45 mmol) was treated substantially as described in Part F of Example 9 to give 4.8 mg (3%) of (R)-8-(5-Fluoro-4-methoxy-2-methyl-phenyl)-4-(1-methoxymethyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (Example 90a): ¹H NMR (300 MHz, CDCl₃) δ ppm 8.43 (d, J=5.13 Hz, 1 H), 7.04 (d, J=5.13 Hz, 1 H), 6.90 (d, J=11.72 Hz, 1 H), 6.82 (d, J=8.42 Hz, 1 H), 6.16 (m, 1 H), 4.30 (m, 1 H), 3.89 (s, 3 H), 3.72 (m, 1 H), 3.27 (s, 3 H), 2.41 (s, 3 H), 2.03 (m, 3 H), 1.64 (m, 2 H), 1.53 (d, J=6.96 Hz, 3 H). MS (EI) m/z 386.3 [(M+H)⁺, 100].

Example 97 (R,S)-4-(1-ethyl-pentyl)-8-(6-methoxy-2-methyl-pyridin-3-yl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one

[0512] Parts A and B

[0513] 6-Methoxy-2-methyl-3′-nitro-3-H[3,4′]bipyridinyl-2′-one was prepared substantially as described in Example 99a.

[0514] Part C

[0515] Trifluoro-methanesulfonic acid 6-methoxy-2-methyl-3′-nitro-3′H-[3,4′]bipyridinyl ester (0.280 g, 0.71 mmol), prepared substantially as described in Part C of Example 99a, an 1-ethyl-pentyl amine (0.430 g, 2.8 mmol) were treated substantially as described in Part C of Example 99a to produce 0.200 g (51%) of (1-ethyl-pentyl)-6-methoxy-2-methyl-3′-nitro-[3,4′]bipyridinyl-2′-yl)amine.

[0516] Part D

[0517] (1-Ethyl-pentyl)-6-methoxy-2-methyl-3′-nitro-[3,4′]bipyridinyl-2′-yl)amine (0.200 g, 0.56 mmol), and Na₂SO₄ (0.785 g, 4.5 mmol), were treated substantially as described in Part D of Example 99a to give a crude yield of 0.066 g (36%) of 6-methoxy-N²-(1-ethyl-pentyl)-2-methyl-[3,4′]bipyridinyl-2′,3′-diamine; MS (AP) m/z 329.2 [(M+H)⁺, 42].

[0518] Part E

[0519] 6-Methoxy-N²-(1-ethyl-pentyl)-2-methyl-[3,4′]bipyridinyl-2′,3′-diamine (0.066 g, 0.20 mmol) and methyl pyruvate (36 μL, 0.40 mmol) were treated substantially as described in Part E of Example 99a to give 4-(1-ethyl-pentyl)-8-(6-methoxy-2-methyl-pyridin-3-yl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (Example 97): ¹H NMR (300 MHz, CDCl₃) δ 8.51-8.43 (m, 1H), 7.50-7.47 (d, 1H, J=8.5 Hz), 7.16-7.11 (m, 1H), 6.71-6.68 (d, 1H, J=8.1 Hz), 4.01 (s, 3H), 2.48-2.46 (m, 3H), 2.29 (s, 3H), 0.88-0.79 (m, 9H), 0.57-0.49 (m, 4H). MS (AP) 381.1 [(M+H)⁺, 100].

Example 99a (R)-4-(1-cyclopropyl-propyl)-8-(6-methoxy-2-methyl-pyridin-3-yl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one

[0520] Part A

[0521] To a solution of 2-benzyloxy-4-chloro-3-nitro-pyridine (Wilde, et al. WO 99/01454, which is incorporated herein by reference) (1.95 g, 7.4 mmol) in ethanol (10 mL) and toluene (40 mL), was added Na₂CO₃ (9.2 mL, 2M), 2-methoxy-6-methyl pyridine boronic acid (Wilde, et al. WO99/01454) (1.85 g, 11.1 mmol), and Pd(PPh₃)₂Cl₂ (0.31 g, 4.44 mmol) and the mixture was heated at reflux for 5 h. The reaction was cooled and poured into EtOAc and H₂O (500 mL). The EtOAc layer was washed with H₂O, brine, dried Na₂SO₄, filtered and concentrated in vacuo. Purification using flash chromatography (10% EtOAc/hexane) gave 2.5 g (96%) of 2′-benzyl-6-methoxy-2-methyl-3′-nitro-2′,3′-dihydro-[3,4′]bipyridinyl as a viscous oil: MS (AP) m/z 352.5 [(M+H)⁺, 100], 392.9 [(M+H+CH₃CN)⁺, 65]. The purified intermediate was used in the following step.

[0522] Part B

[0523] 2′-Benzyl-6-methoxy-2-methyl-3′-nitro-2′,3′-dihydro-[3,4′]bipyridinyl (2.50 g, 7.1 mmol) was dissolved in TFA (25 mL) and stirred at room temperature for 4 h. The reaction mixture was concentrated in vacuo and the crude product 6-methoxy-2-methyl-3′-nitro-3-H[3,4′]bipyridinyl-2′-one; MS (AP) m/z 262.4 [(M+H)⁺, 100], 303.0 [(M+H+CH₃CN)⁺, 72]. The crude intermediate was used in the following step.

[0524] Part C

[0525] To a solution of 6-methoxy-2-methyl-3′-nitro-3-H[3,4′]bipyridinyl-2′-one (0.300 g, 1.1 mmol) CH₂Cl₂ (20 mL), was added Na₂CO₃ (0.296 g, 2.7 mmol). The reaction was cooled to −78° C., and trifluoromethanesulfonic anhydride (574 μL, 3.4 mmol) was added dropwise. After the addition, the reaction stirred for 15 min at −78° C., then warmed to 0° C. for 1 h. The reaction mixture was filtered and the collected solid was washed with CHCl₃. The filtrate was concentrated in vacuo and dissolved in triethylamine (20 mL) followed by and 1-cyclopropyl propyl amine HCl (0.441 g, 3.3 mmol), and heated to reflux overnight. The reaction was cooled and poured onto ice/H₂O. The mixture was extracted with CH₂Cl₂, washed with H₂O, brine, dried Na₂SO₄, filtered, and concentrated in vacuo. Purification using flash chromatography (10% EtOAc/Hexane) gave 0.138 g (49%) of (1-cyclopropyl-propyl)-(6-methoxy-2-methyl-3′-nitro-[3,4′]bipyridinyl-2′-yl)-amine: MS (AP) m/z 343.1 [(M+H)⁺, 100]. The purified intermediate was used in the following step.

[0526] Part D

[0527] (1-Cyclopropyl-propyl)-(6-methoxy-2-methyl-3′-nitro-[3,4′]bipyridinyl-2′-yl)-amine (0.138, 0.40 mmol) was dissolved in dioxane (10 mL) and H₂O (10 mL), followed by conc. NH₄OH (0.4 mL) and Na₂S₂O₄ (0.57 g, 3.3 mmol) and stirred at room temperature for 4 h. The solution was extracted with EtOAc, washed with H₂O, brine, dried Na₂SO₄, filtered, and concentrated in vacuo to produce in crude yield 0.108 g (86%) of N²-(cyclopropyl-propyl)-6-methoxy-2-methyl-[3,4′]bipyridinyl-2′,3′-diamine: MS (AP) m/z 313.2 [(M+H)⁺, 47]. The crude intermediate was used in the following step.

[0528] Part E

[0529] N²-(cyclopropyl-propyl)-6-methoxy-2-methyl-[3,4′]bipyridinyl-2′,3′-diamine (0.053 g, 0.17 mmol) was dissolved in EtOH (10 mL), followed by methyl pyruvate (31 μL, 0.34 mmol) and heated to reflux overnight. The reaction was concentrated in vacuo and purified by reverse phase prep HPLC to yield 4-(1-cyclopropyl-propyl)-8-(6-methoxy-2-methyl-pyridin-3-yl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (Example 99a). ¹H NMR (300 MHz, CDCl₃) δ 8.48-8.46 (2d, 1H, J=4.7), 7.66-7.63 (d, 1H, J=8.8 Hz, 7.13-7.12 (d, 1H, J=4.7 Hz), 6.82-6.79 (d, 1H, J=8.4 Hz), 5.11-4.91, 4.52-4.42 (2m, 1H), 4.06 (s, 3H), 2.50 (s, 3H), 2.38 (s, 3H), 2.37-2.18 (m, 2H), 2.09-1.9 (m, 1H), 0.9-0.85 (t, 3H, J=7.4 Hz), 0.80-0.70 (m, 1H), 0.51-0.42 (m, 1H), 0.40-0.29 (m, 1H), 0.22-0.17 (m, 1H). MS (AP) m/z 365.4 [(M+H)⁺, 100].

Example 101 (R,S)-4-(1-cyclopropyl-butyl)-8-(6-methoxy-2-methyl-pyridin-3-yl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one

[0530] Parts A and B

[0531] 6-Methoxy-2-methyl-3′-nitro-3-H[3,4′]bipyridinyl-2′-one was prepared substantially as described in Example 99a.

[0532] Part C

[0533] Trifluoro-methanesulfonic acid 6-methoxy-2-methyl-3′-nitro-3′H-[3,4′]bipyridinyl ester (0.335 g, 1.3 mmol), prepared substantially as described in Part C of Example 99a, and 1-cyclopropyl-butylamine HCl (0.561 g, 5.2 mmol) were treated substantially as described in Part C of Example 99a to produce 0.075 g (15%) of (1-cyclopropyl-butyl)-6-methoxy-2-methyl-3′-nitro-[3,4′]bipyridinyl-2′-yl)amine: MS (AP) m/z 357.1 [(M+H)⁺, 100].

[0534] Part D

[0535] (1-Cyclopropyl-butyl)-6-methoxy-2-methyl-3′-nitro-[3,4′]bipyridinyl-2′-yl)amine (0.075 g, 0.21 mmol), and Na₂SO₄ (0.296 g, 1.7 mmol), were treated substantially as described in Part D of Example 99a to give a crude yield of 0.055 g (80%) of 6-methoxy-N²-(1-cyclopropyl-butyl)-2-methyl-[3,4′]bipyridinyl-2′,3′-diamine.

[0536] Part E

[0537] 6-Methoxy-N²-(1-cyclopropyl-butyl)-2-methyl-[3,4′]bipyridinyl-2′,3′-diamine (0.055 g, 0.20 mmol) and methyl pyruvate (30 μL, 0.40 mmol) were treated substantially as described in Part E of Example 99a to give 4-(1-cyclopropyl-butyl)-8-(6-methoxy-2-methyl-pyridin-3-yl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (Example 101): ¹H NMR (300 MHz, CDCl₃) δ 8.51-8.43 (2d, 1H, J=4.8 Hz), 7.48-7.46 (d, 1H, J=8.4), 7.12-7.10 (m, 1H), 6.70-6.68 (d, 1H, J=8.4 Hz), 5.17-5.09, 4.60-4.53 (2m, 1H), 4.01 (s,3H), 3.17-3.13 (m, 2H), 2.50 (s, 3H), 2.31 (s, 3H), 2.22-2.15 (m, 3H), 0.92-0.87 (t, 3H, J=7.3 Hz), 0.79-0.73 (m, 1H), 0.53-0.43 (m, 1H), 0.40-0.38 (m, 1H), 0.21-0.17 (m, 1H). MS (AP) 379.1 [(M+H)⁺, 100].

Example 105a (R)-4-(2-methoxy-1-methyl-ethyl)-8-(6-methoxy-2-methyl-pyridyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one

[0538] Parts A and B

[0539] 6-Methoxy-2-methyl-3′-nitro-3-H[3,4′]bipyridinyl-2′-one was prepared substantially as described in Example 99a.

[0540] Part C

[0541] Trifluoro-methanesulfonic acid 6-methoxy-2-methyl-3′-nitro-3′H-[3,4′]bipyridinyl ester (0.280 g, 0.71 mmol), prepared as substantially described in Part C of Example 99a, and 2-methoxy-1-methyl-ethylamine HCl (0.358 g, 2.8 mmol) were treated substantially as described in Part C of Example 99a to produce 0.070 g (30%) of (2-methoxy-1-methyl-ethyl)-6-methoxy-2-methyl-3′-nitro-[3,4′]bipyridinyl-2′-yl)amine: MS (AP) m/z 333.4 [(M+H)⁺, 100].

[0542] Part D

[0543] (2-Methoxy-1-methyl-ethyl)-6-methoxy-2-methyl-3′-nitro-[3,4′]bipyridinyl-2′-yl)amine (0.070 g, 0.21 mmol), and Na₂SO₄ (0.296 g, 1.7 mmol), were treated substantially as described in Part D of Example 99a to give a crude yield of 0.054 g (85%) of 6-methoxy-N²-(2-methoxy-1-methyl-ethyl)-2-methyl-[3,4′]bipyridinyl-2′,3′-diamine: MS (AP) m/z 303.2 [(M+H)⁺, 100].

[0544] Part E

[0545] 6-Methoxy-N²-(2-methoxy-1-methyl-ethyl)-2-methyl-[3,4′]bipyridinyl-2′,3′-diamine (0.054 g, 0.18 mmol) and methyl pyruvate (32 μL, 0.36 mmol) were treated substantially as described in Part E of Example 99a to give 4-(2-methoxy-1-methyl-ethyl)-8-(6-methoxy-2-methyl-pyridyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (Example 105a): ¹H NMR (300 MHz, CDCl₃) δ 8.57-8.56 (d, 1H, J=4.7 Hz), 7.78-7.75 (d, 1H, J=8.5 Hz), 7.16-7.14 (d, 1H, J=5.1 Hz), 6.91-6.88 (d, 1H, J=8.7 Hz), 4.44-4.38 (t, 1H, J=9.1 Hz), 4.11 (s, 3H), 3.79-3.74 (m, 2H), 3.34 (s, 3H), 2.48 (s, 3H), 2.42 (s, 3H), 1.62-1.59 (d, 3H), J=7.0 Hz). MS (AP) 355.6 [(M+H)⁺, 100].

Example 113 (R,S)-4-sec-butyl-8-(2-chloro-4-difluoromethoxy-phenyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one

[0546] Part A

[0547] To a solution of 2-benzyloxy-4-chloro-3-nitro-pyridine (Wilde, et al. WO 99/01454, which is incorporated herein by reference) (6.59 g, 24.9 mmol) in DME/H₂O, was added 2-chloro-4-difluoromethoxy-phenylboronic acid (Wilde, et al. WO 99/01454) (5.54 g, 24.9 mmol), Ba(OH)₂ 8H₂O (7.86 g, 24.9 mmol), and Pd(PPh₃)₂Cl₂ (1.01 g, 1.45 mmol) and the mixture was heated at reflux for 5 h. The reaction was cooled and poured into EtOAc and H₂O (500 mL). The EtOAc layer was washed with H₂O, brine, dried Na₂SO₄, filtered and concentrated in vacuo to give 6.9 g (68%) of 2-benzyloxy-4-(2-chloro-4-difluoromethoxy-phenyl)-3-nitro-pyridine as a viscous oil; MS(AP) m/z 408.9 [(M+H)⁺, 100].

[0548] Part B

[0549] 2-Benzyloxy-4-(2-chloro-4-difluoromethoxy-phenyl)-3-nitro-pyridine(6.90 g, 17.0 mmol) was dissolved in TFA (25 mL) and stirred at room temperature for 4 h. The reaction mixture was concentrated in vacuo. Purification using flash chromatography (15% MeOH/DCM) gave 1.00 g (19%) of 4-(2-chloro-4-difluoromethoxy-phenyl)-3-nitro-3H-pyridin-2-one as an orange solid: MS(AP) m/z 316.9 [(M+H)⁺, 98], 359.8 [(M+H+CH₃CN)⁺, 100].

[0550] Part C

[0551] To 10 mL of POCl₃ was added 4-(2-chloro-4-difluoromethoxy-phenyl)3-nitro-3H-pyridin-2-one (0.20 g, 0.63 mmol), followed by the addition of DMF (1-2 mL) and the reaction refluxed overnight. The reaction mixture was cooled to room temperature and poured over ice/H₂O (200 mL). The solution was extracted with EtOAc, washed H₂O, brine, dried Na₂SO₄, filtered, and concentrated in vacuo to give 0.176 g (96%) of 2-chloro-4-(2-chloro-4-difluoromethoxy-phenyl)-3-nitro-2,3-dihydro-pyridine as brown viscous oil.

[0552] Part D

[0553] 2-Chloro-4-(2-chloro-4-difluoromethoxy-phenyl)-3-nitro-2,3-dihydro-pyridine (0.176 g, 0.53 mmol) was dissolved in acetonitrile (20 mL), followed by the addition of sec butylamine (106 μL, 1.06 mmol) and Hunig's base (184 μL, 1.06 mmol). The reaction was stirred at reflux for 64 h. The solution was cooled to room temperature, extracted with EtOAc/H₂O, organic layer was then washed with 1N HCl and made basic with 1N NaOH. The organic layer was washed with brine, dried Na₂SO₄, filtered and concentrated to yield 0.163 g (83%) of sec-butyl-[4-(chloro-4-difluoromethoxy-phenyl)-3-nitro-2,3-dihydro-pyridin-2-yl]-amine as a yellow oil; MS (AP) 413.0 [(M+H+CH₃CN)⁺, 50].

[0554] Part E

[0555] Sec-butyl-[4-(chloro-4-difluoromethoxy-phenyl)-3-nitro-2,3-dihydro-pyridin-2-yl]-amine (0.163, 0.44 mmol) was dissolved in dioxane (10 mL) and H₂O (10 mL), followed by conc. NH₄OH (0.4 mL) and Na₂S₂O₄ (0.62 g, 3.55 mmol) and stirred at room temperature for 4 h. The solution was extracted with EtOAc, washed with H₂O, brine, dried Na₂SO₄, filtered, and concentrated in vacuo to produce 0.145 g (97%) of N²-sec-butyl-4-(2-chloro-4-difluoromethoxy-phenyl)-2,3-dihydro-pyridine-2,3-diamine as a yellow oil.

[0556] Part F

[0557] Sec-butyl-[4-(chloro-4-difluoromethoxy-phenyl)-3-nitro-2,3-dihydro-pyridin-2-yl]-amine (0.145 g, 0.43 mmol) was dissolved in toluene (20 mL), followed by methyl pyruvate (77 μL, 0.86 mmol) and heated to reflux overnight. The reaction was concentrated in vacuo and purified by reverse phase prep HPLC giving 4-sec-butyl-8-(2-chloro-4-difluoromethoxy-phenyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (Example 113): ¹H NMR (300 MHz, CDCl₃) δ 8.53-8.52 (d, 1H, J=4.8 Hz), 7.35-7.32 (m, 2H), 7.19-7.13 (m, 2H), 6.85-6.36 (t, 1H, J=73.2 Hz), 2.47 (s, 3H), 2.40-2.20 (m, 1H), 2.10-2.07 (m,1H), 1.65-1.63 (d, 3H, J=6.9 Hz), 0.89-0.84 (t, 3H, J=3.7). MS(AP) m/z 394.2 [(M+H)⁺, 100], 435.3 [(M+H+CH₃CN)⁺, 10].

Example 115a (S)-8-(2-Chloro-4-difluoromethoxy-phenyl)-4-(1-cyclopropyl-propyl)2-methyl-4H-pyrido[2,3-b]pyrazin-3-one

[0558] Parts A and B

[0559] 4-(2-Chloro-4-difluoromethoxy-phenyl)-3-nitro-3H-pyridin-2-one was prepared substantially as described in Example 113.

[0560] Part C

[0561] Trifluoro-methanesulfonic acid 4-(2-chloro-4-difluroromethoxy-phenyl)-3-nitro-pyridin-2-yl ester (0.269 g, 0.60 mmol), prepared substantially as described in Part C of Example 115b, and 1-cyclopropyl-proply amine HCl (0.162 g, 1.2 mmol) were treated in the same manner as in Part C of Example 115b with the exception that the crude product was purified using flash chromatography (10% EtOAc/Hexane) to produce 0.138 g (67%) of [4-2-chloro-4-difluoromethoxy-phenyl)-3-nitro-pyridin-2-yl]-(1-cyclopropyl-propyl) amine: MS (AP) m/z 398.0 [(M+H)⁺, 100).

[0562] Part D

[0563] [4-(2-Chloro[4[difluoromethoxy-phenyl)-3-nitro-pyridin-2-yl]-(1-cyclopropyl-propyl)-amine (0.138 g, 0.40 mmol), and Na₂SO₄ (0.567 g, 8.07 mmol), were treated as in Part E of Example 113 to give in crude yield 0.170 g (116%) of 4-(2-chloro-4-difluoromethoxy-phenyl)-N²-(1-cyclopropyl-propyl)-pyridine-2,3-diamine: MS (AP) m/z 368.1 [(M+H)⁺, 40].

[0564] Part E

[0565] 4-(2-chloro-4-difluoromethoxy-phenyl)-N²-(1-cyclopropyl-propyl)-pyridine-2,3-diamine (0.088 g, 0.24 mmol) and methyl pyruvate (140 μL, 1.54 mmol) were treated as in Part F of Example 113 with the exception that ethanol was used as the solvent, gave 8-(2-Chloro-4-difluoromethoxy-phenyl)-4-(1-cyclopropyl-propyl)2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (Example 115a): ¹H NMR (300 MHz, CDCl₃) δ 8.48-8.46 (2d, 1H, J=4.7 Hz), 7.37-7.33 (m, 2H), 7.19-7.14 (m, 2H), 6.86-6.37 (t,1H, J=73.3 Hz), 5.16-4.92, 4.90-4.41 (2m, 1H), 2.57 (s, 3H), 2.49-2.38 (m, 1H), 2.29-2.19 (m, 1H), 2.10-1.93 (m, 1H), 0.90-0.85 (t, 3H, J=7.3), 0.80-0.71 (m, 1H), 0.59-0.50 (m, 1H), 0.49-0.48 (m, 1H), 0.23-0.18 (m, 1H). MS (AP) m/z 420.1 [(M+H)⁺, 100].

Example 115b (R)-8-(2-Chloro-4-difluoromethoxy-phenyl)-4-(1-cyclopropyl-propyl)2-methyl-4H-pyrido[2,3-b]pyrazin-3-one

[0566] Part A

[0567] To a solution of 2-benzyloxy-4-chloro-3-nitro-pyridine (Wilde, et al. WO 99/01454, which is incorporated herein by reference) (5.0 g, 18.9 mmol) in DME/H₂O, was added 2-chloro-4-difluoromethoxy-phenylboronic acid (Wilde, et al. WO 99/01454, which is incorporated by reference herein in its entirety) (4.20 g, 18.9 mmol), Ba(OH)₂ 8H₂O (5.96 g, 18.9 mmol), and Pd(PPh₃)₂Cl₂ (0.769 g, 1.10 mmol) were treated as in Part A of Example 113 to give 5.40 g (70%) of 2-benzyloxy-4-(2-chloro-4-difluoromethoxy-phenyl)-3-nitro-pyridine as a viscous oil. The crude intermediate was used in the following step.

[0568] Part B

[0569] 2-Benzyloxy-4-(2-chloro-4-difluoromethoxy-phenyl)-3-nitro-pyridine (5.40 g, 13.3 mmol) and TFA (25 mL) were treated as in Part B of Example 113 with the exception that the crude product was isolated as 3.90 g (93%) of 4-(2-chloro-4-difluoromethoxy-phenyl)-3-nitro-3H-pyridin-2-one: MS(AP) m/z 317.0 [(M+H)⁺, 90], 357.9 [(M+H+CH₃CN)⁺, 100].

[0570] Part C

[0571] To a solution of 2-benzyloxy-4-(2-chloro-4-difluoromethoxy-phenyl)-3-nitro-pyridin-2-one (0.364 g, 1.2 mmol) CH₂Cl₂ (20 mL), was added Na₂CO₃ (0.299 g, 2.94 mmol). The reaction was cooled to −78° C., and trifluoromethanesulfonic anhydride (576 μL, 3.6 mmol) was added dropwise. After the addition, the reaction stirred for 15 min at −78° C., then warmed to 0° C. for 1 h. The reaction mixture was filtered and the collected solid was washed with CHCl₃. The filtrate was concentrated in vacuo and dissolved in toluene (20 mL) followed by Et₃N(231 μL, 1.7 mmol) and 1-cyclopropyl propyl amine HCl (0.224 g, 1.7 mmol), and heated at 130° C. overnight. The reaction was cooled and poured onto ice/H₂O. The mixture was extracted with CH₂Cl₂, washed with H₂O, brine, dried Na₂SO₄, filtered, and concentrated in vacuo to produce in crude yield 0.301 g, (91%) of [4-(2-chloro[4[difluoromethoxy-phenyl)-3-nitro-pyridin-2-yl]-(1-cyclopropyl-propyl)-amine. MS(AP) m/z 398.0 [(M+H)⁺, 100]. The crude intermediate was used in the following step.

[0572] Part D

[0573] [4-(2-Chloro[4[difluoromethoxy-phenyl)-3-nitro-pyridin-2-yl]-(1-cyclopropyl-propyl)-amine (0.301 g, 0.76 mmol), and Na₂SO₄ (1.07 g, 6.12 mmol), were treated substantially as described in Part E of Example 113 to give 0.284 g (91%) of 4-(2-chloro-4-difluoromethoxy-phenyl)-N²-(1-cyclopropyl-propyl)-pyridine-2,3-diamine. The crude intermediate was used in the following step.

[0574] Part E

[0575] 4-(2-Chloro-4-difluoromethoxy-phenyl)-N²-(1-cyclopropyl-propyl)-pyridine-2,3-diamine (0.284 g, 0.77 mmol) and methyl pyruvate (140 μL, 1.54 mmol) were treated substantially as described in Part F of Example 113 to give 8-(2-Chloro-4-difluoromethoxy-phenyl)-4-(1-cyclopropyl-propyl)2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (Example 115b): ¹H NMR (300 MHz, CDCl₃) δ 8.52-8.46 (2d, 1H, J=4.8), 7.37-7.32 (m, 2H), 7.26-7.14 (m, 2H), 6.85-6.37(t,1H, J=73.3 Hz), 5.09-4.95, 4.75-4.2 (2m, 1H), 2.48 (s, 3H), 2.4-2.25 (m, 1H), 2.23-2.16 (m, 1H), 2.13-1.93 (m, 1H), 0.90-0.85 (t, 3H, J=7.3 Hz), 0.80-0.67 (m, 1H), 0.57-0.42 (m, 1H), 0.40-0.29 (m, 1H), 0.24-0.18 (m, 1H). MS (AP) m/z 420.2 [(M+H)⁺, 100], 461.3 [(M+H+CH₃CN)⁺, 20].

Example 117 (R,S)-8-(2-Chloro-4-difluoromethoxy-phenyl)-4-(1-cyclopropyl-butyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one

[0576] Parts A and B

[0577] 4-(2-Chloro-4-difluoromethoxy-phenyl)-3-nitro-3H-pyridin-2-one was prepared substantially as described in Example 113.

[0578] Part C

[0579] Trifluoro-methanesulfonic acid 4-(2-chloro-4-difluroromethoxy-phenyl)-3-nitro-pyridin-2-yl ester (0.369 g, 0.83 mmol), prepared substantially as described in Part C of Example 155b, and 1-cyclo-proply-butylamine HCl (0.246 g, 1.7 mmol) were treated substantially as described in Part C of Example 115b to produce in crude yield 0.380 g (111%) of [4-2-chloro-4-difluoromethoxy-phenyl)-3-nitro-pyridin-2-yl]-(1-cyclopropyl-butyl)-amine: MS (AP) m/z 412.0 [(M+H)⁺, 100].

[0580] Part D

[0581] [4-2-Chloro-4-difluoromethoxy-phenyl)-3-nitro-pyridin-2-yl]-(1-cyclopropyl-butyl)-amine (0.380 g, 0.92 mmol), and Na₂SO₄ (1.30 g, 7.5 mmol), were treated substantially as described in Part E of Example 113 to give a crude yield of 0.300 g (86%) of 4-(2-chloro-4-difluoromethoxy-phenyl)-N²-(1-cyclopropyl-butyl)-pyridine-2,3-diamine.

[0582] Part E

[0583] 4-(2-Chloro-4-difluoromethoxy-phenyl)-N²-(1-cyclopropyl-butyl)-pyridine-2,3-diamine (0.300 g, 0.79 mmol) and methyl pyruvate (142 μL, 1.58 mmol) were treated substantially as described in Part F of Example 113 to give 8-(2-chloro-4-difluoromethoxy-phenyl)-4-(1-cyclopropyl-butyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (Example 117). ¹H NMR (300 MHz, CDCl₃) δ 8.47-8.46 (2d, 1H, J=4.8 Hz), 7.37-7.28 (m, 2H), 7.20-7.10 (m, 2H), 6.85-6.37 (t, 1H, J=72.8 Hz), 5.18-5.02, 4.60-4.51 (2m, 1H), 2.49 (s, 3H), 2.40-2.32 (m, 1H), 2.29-2.17 (m, 2H), 2.10-2.00 (m, 1H), 0.92-0.88 (t, 3H, J=7.4 Hz), 0.87-0.77 (m, 1H), 0.59-0.42 (m, 2H), 0.40-0.31 (m, 2H). MS (AP) m/z 434.1 [(M+H)⁺, 100)].

Example 121a (R)-8-(2-chloro-4-difluoromethoxy-phenyl)-4-(2-methoxy-1-methyl-ethyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one

[0584] Parts A and B

[0585] 4-(2-Chloro-4-difluoromethoxy-phenyl)-3-nitro-3H-pyridin-2-one was prepared substantially as described in Example 113.

[0586] Part C

[0587] Trifluoro-methanesulfonic acid 4-(2-chloro-4-difluroromethoxy-phenyl)-3-nitro-pyridin-2-yl ester (0.332 g, 0.74 mmol), prepared substantially as described in Part C of Example 115b, and 2-methoxy-1-methyl-ethylamine HCl (0.207 g, 1.5 mmol) were treated substantially as described in Part C of Example 115b to produce 0.231 g (78%) of [4-2-chloro-4-difluoromethoxy-phenyl)-3-nitro-pyridin-2-yl]-(2-methoxy-1-methyl-ethyl)-amine: MS (AP) m/z 387.9 [(M+H)⁺, 100].

[0588] Part D

[0589] [4-2-Chloro-4-difluoromethoxy-phenyl)-3-nitro-pyridin-2-yl]-(2-methoxy-1-methyl-ethyl)-amine (0.231 g, 0.58 mmol), and Na₂SO₄ (0.809 g, 4.7 mmol), were treated substantially as described in Part E of Example 113 to give 0.149 g (72%) of 4-(2-chloro-4-difluoromethoxy-phenyl)-N²-(2-methoxy-1-methyl-ethyl)-pyridine-2,3-diamine: MS (AP) m/z 358.0 [(M+H)⁺, 100]. Crude intermediate was taken on to Part E

[0590] Part E

[0591] 4-(2-Chloro-4-difluoromethoxy-phenyl)-N²-(2-methoxy-1-methyl-ethyl)-pyridine-2,3-diamine (0.149 g, 0.42 mmol) and methyl pyruvate (75 μL, 0.83 mmol) were treated substantially as described in Part F of Example 113 to give 8-(2-chloro-4-difluoromethoxy-phenyl)-4-(2-methoxy-1-methyl-ethyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (Example 121a): ¹H NMR (300 MHz, CDCl₃): δ 8.54-8.53 (d, 1H, J=4.8 Hz), 7.34-7.32 (m, 2H), 7.21-7.13 (m, 2H), 6.85-6.36 (t, 1H, J=73.2 Hz), 4.41-4.37 (m, 1H), 3.82-3.76 (m, 2H), 3.34 (s, 3H), 2.47 (s, 3H), 1.62 (d, 3H, J=6.9 Hz). MS (AP) m/z 410.0 [(M+H)⁺, 100].

Example 122a (R)-8-(2-Chloro-4-difluoromethoxy-phenyl)-4-(1-methoxymethyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one

[0592] Parts A and B

[0593] 4-(2-Chloro-4-difluoromethoxy-phenyl)-3-nitro-3H-pyridin-2-one was prepared substantially as described in Example 113.

[0594] Part C

[0595] Trifluoro-methanesulfonic acid 4-(2-chloro-4-difluroromethoxy-phenyl)-3-nitro-pyridin-2-yl ester (0.405 g, 0.9 mmol), prepared substantially as described in Part C of Example 155b, and 2-methoxymethyl-propylamine HCl (0.252 g, 1.8 mmol) were treated in the same manner as in Part C of Example 115b to produce in crude yield 0.350 g (97%) of [4-2-chloro-4-difluoromethoxy-phenyl)-3-nitro-pyridin-2-yl]-(1-methoxymethyl-propyl) amine. MS (AP) m/z 402.0 [(M+H)⁺, 100].

[0596] Part D

[0597] [4-2-Chloro-4-difluoromethoxy-phenyl)-3-nitro-pyridin-2-yl]-(1-methoxymethyl-propyl) amine (0.350 g, 0.87 mmol), and Na₂SO₄ (1.23 g, 7.04 mmol), were treated substantially as described in Part E of Example 113 to give a crude yield of 0.268 g (83%) of 4-(2-chloro-4-difluoromethoxy-phenyl)-N²-(1-methoxymethyl-propyl)-pyridine-2,3-diamine; MS (AP) m/z 372.0 [(M+H)⁺, 100].

[0598] Part E

[0599] 4-(2-Chloro-4-difluoromethoxy-phenyl)-N²-(1-methoxymethyl-propyl)-pyridine-2,3-diamine (0.268 g, 0.72 mmol) and methyl pyruvate (130 μL, 1.44 mmol) were treated substantially as described in Part F of Example 113 to give 8-(2-chloro-4-difluoromethoxy-phenyl)-4-(1-methoxymethyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (Example 122a): ¹H NMR (300 MHz, CDCl₃) δ □8.54-8.51 (m, 1H), 7.33-7.32 (m,2H), 7.21-7.14 (m, 2H), 6.85-6.37 (t, 1H, J=72.9 Hz), 6.21-6.19, 5.64-5.58 (2m, 1H), 4.40-4.31 (m, 1H), 3.92-3.79 (m, 1H), 3.33 (s, 3H), 2.48 (s, 3H), 2.30-2.20 (m, 1H),2.13-1.96 (m, 1H), 0.90-0.85 (t, 3H, J=7.7 Hz). MS (AP) m/z 424.1 [(M+H)⁺, 100].

Example 122b (S)-8-(2-Chloro-4-difluoromethoxy-phenyl)-4-(1-methoxymethyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one

[0600] Parts A and B

[0601] 4-(2-Chloro-4-difluoromethoxy-phenyl)-3-nitro-3H-pyridin-2-one was prepared substantially as described in Example 113.

[0602] Part C

[0603] Trifluoro-methanesulfonic acid 4-(2-chloro-4-difluroromethoxy-phenyl)-3-nitro-pyridin-2-yl ester (0.473 g, 1.1 mmol), prepared substantially as described in Part C of Example 115b, and 2-methoxymethyl-propylamine HCl (0.295 g, 2.2 mmol) were treated in the same manner as in Part C of Example 115b to produce 0.380 g (86%) of [4-2-chloro-4-difluoromethoxy-phenyl)-3-nitro-pyridin-2-yl]-(1-methoxymethyl-propyl) amine: MS (AP) m/z 402.0 [(M+H)⁺, 100].

[0604] Part D

[0605] [4-2-Chloro-4-difluoromethoxy-phenyl)-3-nitro-pyridin-2-yl]-(1-methoxymethyl-propyl) amine (0.38 g, 0.95 mmol), and Na₂SO₄ (1.33 g, 7.6 mmol), were treated substantially as described in Part E of Example 113 to give a crude yield of 0.366 g of 4-(2-chloro-4-difluoromethoxy-phenyl)-N²-(1-methoxymethyl-propyl)-pyridine-2,3-diamine: MS (AP) m/z 372.0 [(M+H)⁺, 100].

[0606] Part E

[0607] 4-(2-Chloro-4-difluoromethoxy-phenyl)-N²-(1-methoxymethyl-propyl)-pyridine-2,3-diamine (0.366 g, 0.99 mmol) and methyl pyruvate (178 μL, 1.97 mmol) were treated as in Part F of Example 133 to give 8-(2-chloro-4-difluoromethoxy-phenyl)-4-(1-methoxymethyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (Example 122b): ¹H NMR (300 MHz, CDCl₃) δ 8.56-8.51 (m, 1H), 7.33-7.30 (m, 2H), 7.27-7.23 (m, 2H), 6.82-6.33 (t, 1H, J=72.9 Hz), 6.20-6.18, 5.62-5.57 (2m, 1H), 4.38-4.32 (m,1H), 3.93-3.80 (m, 1H), 3.33 (s, 3H), 2.47 (s, 3H), 2.08-2.00 (m, 2H), 0.90-0.88 (t, 3H, J=6.3 Hz). MS (AP) 424.1 [(M+H)⁺, 100].

Example 131a (S)-8-(2-chloro-4-trifluoromethyl-phenyl)-4-(1-cyclopropyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one

[0608] Part A

[0609] 2-Benzyloxy-4-chloro-3-nitro-pyridine (Wilde, et al. WO 99/01454, which is incorporated herein by reference in its entirety) (2.0 g, 7.56 mmol) and 2-chloro-4-trifluoromethylphenylboronic acid (2.31 g, 11.3 mmol) were treated substantially as described in Part A of Example 19a to give 2.44 g (79%) of 2-benzyloxy-4-(2-chloro-4-trifluoromethyl-phenyl)-3-nitro-pyridine: MS (AP) m/z 408.8 [(M+H)⁺, 72].

[0610] Part B

[0611] 2-Benzyloxy-4-(2-chloro-4-trifluoromethyl-phenyl)-3-nitro-pyridine (2.44 g, 5.97 mmol) was treated as in Part B of Example 19a to give 2.01 g (100%) of 4-(2-chloro-4-trifluoromethyl-phenyl)-3-nitro-1H-pyridin-2-one: MS (AP) m/e 318.6 [(2M−H)⁻, 100].

[0612] Part C

[0613] Trifluoro-methanesulfonic acid 4-(2-chloro-4-trifluoromethyl-phenyl)-3-nitro-pyridin-2-yl-ester (0.62 g, 1.38 mmol), prepared substantially as described in Part C of Example 19a, and 1-cyclopropyl-propylamine HCl (0.37 g, 2.75 mmol) were treated substantially as described in Part C of Example 19a to produce 0.55 g (100%) of [4-(2-chloro-4-trifluoromethyl-phenyl)-3-nitro-pyridin-2-yl]-(1-cyclopropyl-propyl)-amine: MS (AP) m/z 399.8 [(M+H)⁺, 25].

[0614] Part D

[0615] [4-(2-Chloro-4-trifluoromethyl-phenyl)-3-nitro-pyridin-2-yl]-(1-cyclopropyl-propyl)-amine (0.55 g, 1.38 mmol) and Na₂S₂O₄ (1.93 g, 11.1 mmol) were treated substantially as in Part E of Example 9 to yield 94% of 4-(2-chloro-4-trifluoromethyl-phenyl)-N²-(1-cyclopropyl-propyl)-pyridine-2,3-diamine: MS (AP) m/z 369.8 [(M+H)⁺, 100].

[0616] Part E

[0617] 4-(2-Chloro-4-trifluoromethyl-phenyl)-N²-(1-cyclopropyl-propyl)-pyridine-2,3-diamine (0.31 g, 0.86 mmol) was treated substantially as described in Part F of Example 9 to give 8.2 mg (2%) of 8-(2-chloro-4-trifluoromethyl-phenyl)-4-(1-cyclopropyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (Example 131a): ¹H NMR (300 MHz, CDCl₃): δ 8.5 (d, 1H), 7.77 (s, 1H), 7.6 (d, 1H), 7.5 (d, 1H), 7.17 (s, 1H), 5.0 (q, 1H), 4.45 (q, 1H), 2.45 (s, 2H), 2.4-2.10 (m, 1H), 1.3 (s, 3H), 0.90 (t, 3H), 0.70 (m, 1H), 0.50-0.30 (m, 2H). MS (AP) m/z 421.9 [(M+H)⁺, 100].

Example 137a (R)-8-(2-chloro-4-trifluoromethyl-phenyl)-4-(2-methoxy-1-methyl-ethyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one

[0618] Part A

[0619] 2-Benzyloxy-4-chloro-3-nitro-pyridine (Wilde, et al. WO 99/01454, which is incorporated herein by reference in its entirety) (2.0 g, 7.56 mmol) and 2-chloro-4-trifluoromethylphenylboronic acid (2.31 g, 11.3 mmol) were treated as in Part A of Example 19a to give 2.44 g (79%) of 2-benzyloxy-4-(2-chloro-4-trifluoromethyl-phenyl)-3-nitro-pyridine: MS (AP) m/z 408.8 [(M+H)⁺, 72].

[0620] Part B

[0621] 2-Benzyloxy-4-(2-chloro-4-trifluoromethyl-phenyl)-3-nitro-pyridine (2.44 g, 5.97 mmol) was treated as in Part B of Example 19a to give 2.01 g (100%) of 4-(2-chloro-4-trifluoromethyl-phenyl)-3-nitro-1H-pyridin-2-one: MS (AP) m/e 318.6 [(2M−H)⁻, 100].

[0622] Part C

[0623] Trifluoro-methanesulfonic acid 4-(2-chloro-4-trifluoromethyl-phenyl)-3-nitro-pyridin-2-yl-ester (0.50 g, 1.11 mmol), prepared substantially as described in Part C of Example 19a, and 2-methoxy-1-methyl-ethylamine HCl (0.28 g, 2.22 mmol) were treated in the same manner as in Part C of Example 19a to produce 0.45 g (100%) of [4-(2-chloro-4-trifluoromethyl-phenyl)-3-nitro-pyridin-2-yl]-(2-methoxy-1-methyl-ethyl)-amine: MS (AP) m/z 389.8 [(M+H)⁺, 100].

[0624] Part D

[0625] [4-(2-Chloro-4-trifluoromethyl-phenyl)-3-nitro-pyridin-2-yl]-(2-methoxy-1-methyl-ethyl)-amine (0.45 g, 1.15 mmol) and Na₂S₂O₄ (1.62 g, 9.32 mmol) were treated substantially as described in Part E of Example 9 to yield 0.31 g (74%) of 4-(2-chloro-4-trifluoromethyl-phenyl)-N²-(2-methoxy-1-methyl-ethyl)-pyridine-2,3-diamine: MS (AP) m/z 359.8 [(M+H)⁺, 97].

[0626] Part E

[0627] 4-(2-Chloro-4-trifluoromethyl-phenyl)-N²-(2-methoxy-1-methyl-ethyl)-pyridine-2,3-diamine (0.31 g, 0.86 mmol) was treated substantially as described in Part F of Example 9 to give 8.2 mg (2%) of 8-(2-chloro-4-trifluoromethyl-phenyl)-4-(2-methoxy-1-methyl-ethyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (Example 137a): ¹H NMR (300 MHz, CDCl₃): δ 8.5 (d, 1H), 7.7 (s, 1H), 7.6 (d, 1H), 7.4 (d, 1H), 7.20 (d, 1H), 4.4 (t, 1H), 3.8 (q, 1H), 3.3 (s, 3H), 2.5 (bs, 1H), 2.4 (s, 3H), 1.6 (d, 3H). MS (AP) m/z 411.8 [(M+H)⁺, 100].

Example 138a (R)-8-(2-chloro-4-trifluoromethyl-phenyl)-4-(1-methoxymethyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one

[0628] Parts A and B

[0629] 4-(2-Chloro-4-trifluoromethyl-phenyl)-3-nitro-1H-pyridin-2-one was prepared substantially as described in Example 137a.

[0630] Part C

[0631] Trifluoro-methanesulfonic acid 4-(2-chloro-4-trifluoromethyl-phenyl)-3-nitro-pyridin-2-yl-ester (0.50 g, 1.11 mmol), prepared substantially as described in Part C of Example 19a, and 1-methoxymethyl-propylamine HCl (0.31 g, 2.22 mmol) were treated substantially as described in Part C of Example 19a to produce 0.40 g (89%) of [4-(2-chloro-4-trifluoromethyl-phenyl)-3-nitro-pyridin-2-yl]-(1-methoxymethyl-propyl)-amine: MS (AP) m/z 403.8 [(M+H)⁺, 98].

[0632] Part D

[0633] [4-(2-Chloro-4-trifluoromethyl-phenyl)-3-nitro-pyridin-2-yl]-(1-methoxymethyl-propyl)-amine (0.40 g, 1.0 mmol) and Na₂S₂O₄ (1.39 g, 8.0 mmol) were treated substantially as described in Part E of Example 9 to yield 0.29 g (78%) of 4-(2-chloro-4-trifluoromethyl-phenyl)-N²-(1-methoxymethyl-propyl)-pyridine-2,3-diamine: MS (AP) m/z 373.8 [(M+H)⁺, 100].

[0634] Part E

[0635] 4-(2-Chloro-4-trifluoromethyl-phenyl)-N²-(1-methoxymethyl-propyl)-pyridine-2,3-diamine (0.29 g, 0.78 mmol) was treated substantially as described in Part F of Example 9 to give 6.5 mg (2%) of 8-(2-chloro-4-trifluoromethyl-phenyl)-4-(1-methoxymethyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (Example 138a): ¹H NMR (300 MHz, CDCl₃): δ 8.5 (bs, 1H), 7.7 (s, 1H), 7.6 (d, 1H), 7.45 (d, 1H), 7.17 (d, 1H), 6.10 (m, 1H), 4.3 (m, 1H), 3.8 (m, 1H), 3.3 (s, 3H), 2.45 (s, 3H), 2.0 (m, 1H), 1.2 (s, 1H), 0.90 (t, 3H). MS (AP) m/z 425.8 [(M+H)⁺, 100].

Example 243a (S)-8-(2-Chloro-5-fluoro-4-methoxy-phenyl)-4-(1-cyclopropyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one

[0636] Part A and B

[0637] 4-(2-Chloro-5-fluoro-4-methoxy-phenyl)-3-nitro-1H-pyridin-2-one was prepared substantially as described in Example 250.

[0638] Part C

[0639] Trifluoro-methanesulfonic acid 4-(2-chloro-5-fluoro-4-methoxy-phenyl)-3-nitro-pyridin-2-yl ester (0.3 g, 0.70 mmol) and (S)-1-cyclopropyl-propylamine (0.28 g, 2.09 mmol) were treated substantially as described in Part C of Example 19a to produce 30 mg (12%) of crude (S)-[4-(2-chloro-5-fluoro-4-methoxy-phenyl)-3-nitro-pyridin-2-yl]-(1-cyclopropyl-propyl)-amine.

[0640] Part D

[0641] (S)-[4-(2-Chloro-5-fluoro-4-methoxy-phenyl)-3-nitro-pyridin-2-yl]-(1-cyclopropyl-propyl)-amine (30 mg, 0.08 mmol) and SnCl₂ (44 mg, 0.23 mmol) were treated substantially as described in Part D of Example 74a to yield 25 mg (92%) of (S)-4-(2-chloro-5-fluoro-4-methoxy-phenyl)-N²-(1-cyclopropyl-propyl)-pyridine-2,3-diamine.

[0642] Part E

[0643] (S)-4-(2-Chloro-5-fluoro-4-methoxy-phenyl)-N²-(1-cyclopropyl-propyl)-pyridine-2,3-diamine (25 mg, 0.07 mmol) was treated substantially as described in Part F of Example 9 to give 2.5 mg (9%) of (S)-8-(2-chloro-5-fluoro-4-methoxy-phenyl)-4-(1-cyclopropyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (Example 243a): ¹H NMR (400 MHz, CDCl₃) δ ppm 8.47 (d, J=4.89 Hz, 1 H), 7.18 (d, J=4.89 Hz, 1 H), 7.12 (d, J=8.07 Hz, 1 H), 7.09 (d, J=4.40 Hz, 1 H), 4.81 (m, 1 H), 3.96 (s, 3 H), 2.49 (s, 3 H), 2.21 (m, 2 H), 0.86 (t, J=7.46 Hz, 3 H), 0.83 (m, 1 H), 0.71 (m, 1 H), 0.47 (m, 1 H), 0.35 (m, 1 H), 0.15 (m, 1 H). MS (EI) m/z 402.20 [(M+H)+, 100].

Example 250 8-(2-Chloro-5-fluoro-4-methoxy-phenyl)-4-(1-methoxymethyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one

[0644] Part A

[0645] 2-Benzyloxy-4-chloro-3-nitro-pyridine (Wilde, et. al. WO 99/01454) (3.8 g, 14.3 mmol) and 2-chloro-5-fluoro-4-methoxyphenylboronic acid (Preparation 1) (3.8 g, 18.6 mmol) were treated substantially as described in Part A of Example 19a to give 3.5 g (63%) of 2-benzyloxy-4-(2-chloro-5-fluoro-4-methoxy-phenyl)-3-nitro-pyridine: ¹H NMR (400 MHz, CDCl₃) δ ppm 8.30 (d, J=5.4 Hz, 1 H), 7.45-7.42 (m, 2H), 7.40-7.29 (m, 3H), 7.04 (d, J=7.6 Hz, 1 H), 7.00 (d, J=10.8 Hz, 1 H), 6.91 (d, J=5.4 Hz, 1 H), 5.54 (s, 2 H), 3.91 (s, 3 H).

[0646] Part B

[0647] 2-Benzyloxy-4-(2-chloro-5-fluoro-4-methoxy-phenyl)-3-nitro-pyridine (3.5 g, 9.0 mmol) was treated substantially as described in Part B of Example 19a to give 4-(2-chloro-5-fluoro-4-methoxy-phenyl)-3-nitro-1H-pyridin-2-one (2.3 g, 86%): ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.97 (br s, 1H), 7.79 (d, J=6.3 Hz, 1 H), 7.44 (d, J=7.8 Hz, 1 H), 7.38 (d, J=11.3 Hz, 1 H), 6.30 (d, J=6.3 Hz, 1 H), 3.91 (s, 3 H).

[0648] Part C

[0649] Trifluoro-methanesulfonic acid 4-(2-Chloro-5-fluoro-4-methoxy-phenyl)-3-nitro-1H-pyridin-2-one (0.3 g, 0.70 mmol), prepared substantially as described in Part C of Example 19a, and 1-methoxymethyl-propylamine (0.28 g, 2.79 mmol) were treated substantially as described in Part C of Example 19a to produce 35 mg (13%) of crude [4-(2-chloro-5-fluoro-4-methoxy-phenyl)-3-nitro-pyridin-2-yl]-(1-methoxymethyl-propyl)-amine.

[0650] Part D

[0651] [4-(2-Chloro-5-fluoro-4-methoxy-phenyl)-3-nitro-pyridin-2-yl]-(1-methoxymethyl-propyl)-amine (35 mg, 0.09 mmol) and SnCl₂ (51 mg, 0.27 mmol) were treated substantially as described in Part D of Example 74a to yield 30 mg (94%) of 4-(2-Chloro-5-fluoro-4-methoxy-phenyl)-N²-(1-methoxymethyl-propyl)-pyridine-2,3-diamine: MS (EI) m/z 354.22 [(M+H)⁺, 100].

[0652] Part E

[0653] 4-(2-Chloro-5-fluoro-4-methoxy-phenyl)-N²-(1-methoxymethyl-propyl)-pyridine-2,3-diamine (30 mg, 0.084 mmol) was treated substantially as described in Part F of Example 9 to give 3.3 mg (10%) of 8-(2-Chloro-5-fluoro-4-methoxy-phenyl)-4-(1-methoxymethyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (Example 250): ¹H NMR (400 MHz, CDCl₃) δ ppm 8.55 (d, J=4.89 Hz, 1 H), 7.21 (d, J=4.89 Hz, 1 H) 7.11 (d, J=2.94 Hz, 1 H), 7.08 (d, J=2.20 Hz, 1 H), 5.88 (m, 1 H), 4.33 (m, 1 H), 3.95 (s, 3 H), 3.81 (m, 1 H), 3.32 (s, 3 H), 2.48 (s, 3 H), 2.11 (d, J=95.37 Hz, 2 H), 0.86 (t, J=7.46 Hz, 3 H). MS (EI) m/z 406.29 [(M+H)+, 100].

Example 449a (R)-3-Chloro-4-[4-(1-methoxymethyl-propyl)-2-methyl-3-oxo-3,4-dihydro-pyrido[2,3-b]pyrazin-8-yl-benzonitrile

[0654] Part A

[0655] To a solution of POCl₃ (100 mL) was added 2,4-hydroxy-3-nitropyridine (10.0 g, 64.1 mmol) and the reaction heated at reflux overnight. The reaction mixture was cooled and slowly added to an ice-water solution. The solution was extracted with EtOAc and the organic layer was dried (Na₂SO₄), filtered and concentrated in vacuo. The dark brown oil was purified by filtration through silica gel with 50% EtOAc/Hex to yield 4.31 g, 35% of 2,4-dichloro-3-nitropyridine as a dark yellow solid. Reaction was monitored by thin layer chromatography for completion.

[0656] Part B

[0657] 2,4-Dichloro-3-nitropyridine (1.0 g, 5,18 mmol) was dissolved in EtOH (20 mL), followed by the addition of Et₃N (1.05 g, 10.4 mmol) and (R)-1-methoxymethyl-propylamine (0.72 g, 5.18 mmol) and the reaction was heated at 60° C. for 3 h. The reaction was concentrated in vacuo to yield 2.09 g of (R)-(4-chloro-3-nitro-pyridin-2-yl)-(1-methoxymethyl-propyl)-amine as a crude viscous oil: MS (AP) m/z 259.69 [(M+H)+, 97].

[0658] Part C

[0659] (R)-(4-Chloro-3-nitropyridin-2-yl)-(1-methoxymethyl-propyl)-amine (2.09 g, 8.05 mmol) was dissolved in ether (30 mL) and cooled to 0° C. Next, SnCl₂.2H₂O (18.1 g, 80.5 mmol) in conc. HCl (10 mL) was added, dropwise at 0° C. and stirred at room temperature for 4 h. The reaction mixture was poured over ice water containing 50% NaOH solution (20 mL) and extracted with EtOAc (2×). The aqueous layer was filtered through celite, then extracted with EtOAc (2×). The combined organic layers were dried (Na₂SO₄), filtered, and concentrated in vacuo. The crude product was purified by column chromatography (20% EtOAc/Hex) to yield 0.24 g, 13% of (R)-4-chloro-N²-(1-methoxymethyl-propyl)-pyridine-2,3-diamine: MS (AP) m/z 229.71 [(M+H)+, 100].

[0660] Part D

[0661] (R)-4-Chloro-N²-(1-methoxymethyl-propyl)-pyridine-2,3-diamine (0.24 g, 1.04 mmol) was dissolved in n-BuOH, followed by methyl pyruvate (1.07 g, 10.4 mmol) and the reaction was heated at 60° C. for 5 h, before heating at reflux overnight. The reaction was concentrated in vacuo and purified by column chromatography (20% EtOAc/hex) to yield 0.39 g, 100% of (R)-8-chloro-4-(1-methoxymethylpropyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one: MS (AP) m/z 281.74 [(M+H)+, 100].

[0662] Part E

[0663] (R)-8-Chloro-4-(1-methoxymethyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (0.39 g, 1.38 mmol) was dissolved in EtOH/toluene (1:4), followed by Na₂CO₃ (2M, 1.73 mL, 3.46 mmol), 2-chloro-4-cyanophenyl boronic acid (0.38 g, 2.08 mmol) and Pd₂(PPh₃)₂Cl₂ (0.048 g, 0.069 mmol) and refluxed for 5 h. The reaction was cooled to room temperature, extracted with EtOAc, washed with H₂O, brine, dried (MgSO₄), filtered and concentrated in vacuo. Purification by HPLC yielded 13.10 mg, 3% of (R)-3-chloro-4-[4-(1-methoxymethyl-propyl)-2-methyl-3-oxo-3,4-dihydro-pyrido[2,3-b]pyrazin-8-yl-benzonitrile (Ex. 449a): MS (ESI) 382.85 [(M+H)+, 100].

Example 452 8-(5-Chloro-4-methoxy-2-methyl-phenyl)-4-(1-cyclopropyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one

[0664] Part A

[0665] 2-Benzyloxy-4-chloro-3-nitro-pyridine (Wilde, et. al. WO 99/01454) (774 mg, 2.81 mmol) and 2-methyl-5-chloro-4-methoxyphenylboronic acid (prepared as described in Speicher, A.; Kolz, J.; Sambanje, R. P. Synthesis, 2002, 17, 2503) (620 mg, 3.09 mmol) were treated substantially as described in Part A of Example 19a to give 1.15 g (47%) of 2-benzyloxy-4-(5-chloro-4-methoxy-2-methyl-phenyl)-3-nitro-pyridine: ¹H NMR (400 MHz, CDCl₃) δ ppm 8.26 (d, J=5.1 Hz, 1 H), 7.45-7.42 (m, 2H), 7.39-7.30 (m, 3H), 7.13 (s, 1H), 6.82 (d, J=5.1 Hz, 1 H), 6.79 (s, 1 H), 5.54 (s, 2 H), 3.90 (s, 3H), 2.14 (s, 3H).

[0666] Part B

[0667] 2-Benzyloxy-4-(5-chloro-4-methoxy-2-methyl-phenyl)-3-nitro-pyridine (1.0 g, 2.6 mmol) was treated substantially as described in Part B of Example 19a to give 4-(5-chloro-4-methoxy-2-methyl-phenyl)-3-nitro-1H-pyridin-2-one (0.75 g, 98%): MS (EI) m/z 295.14 [(M+H)⁺, 100].

[0668] Part C

[0669] Trifluoro-methanesulfonic acid 4-(5-chloro-4-methoxy-2-methyl-phenyl)-3-nitro-pyridin-2-yl ester (0.33 g, 0.76 mmol), prepared substantially as described in Part C of Example 19a, and 1-cyclopropyl-propylamine (0.25 g, 1.92 mmol) were treated substantially as described in Part C of Example 19a to produce 0.13 g (45%) of crude (1-cyclopropyl-propyl)-[4-(5-fluoro-4-methoxy-2-methyl-phenyl)-3-nitro-pyridin-2-yl]-amine: MS (EI) m/z 376.2 [(M+H)⁺, 100].

[0670] Part D

[0671] (1-Cyclopropyl-propyl)-[4-(5-fluoro-4-methoxy-2-methyl-phenyl)-3-nitro-pyridin-2-yl]-amine (0.13 g, 0.34 mmol) and SnCl₂ (0.19 g, 1.0 mmol) were treated substantially as described in Part D of Example 74a to yield 0.12 g (96%) of 4-(5-chloro-4-methoxy-2-methyl-phenyl)-N²-(1-cyclopropyl-propyl)-pyridine-2,3-diamine.

[0672] Part E

[0673] 4-(5-Chloro-4-methoxy-2-methyl-phenyl)-N²-(1-cyclopropyl-propyl)-pyridine-2,3-diamine (0.12 g, 0.33 mmol) was treated substantially as described in Part F of Example 9 to give 30 mg (23%) of 8-(5-chloro-4-methoxy-2-methyl-phenyl)-4-(1-cyclopropyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (Example 452): ¹H NMR (400 MHz, CDCl₃) δ ppm 8.48 (d, J=4.89 Hz, 1 H), 7.24 (s, 1 H), 7.12 (d, J=4.89 Hz, 1 H), 6.87 (s, 1 H), 4.79 (m, 1 H), 3.96 (s, 3 H), 2.51 (s, 3 H), 2.26 (m, 2 H), 2.10 (s, 3 H), 0.88 (m, 1 H), 0.87 (t, J=6.72 Hz, 3 H), 0.70 (m, 1 H), 0.49 (m, 1 H), 0.34 (m, 1 H), 0.17 (m, 1 H). MS (EI) m/z 400.21 [(M+H)+, 100].

Example 459 8-(5-Chloro-4-methoxy-2-methyl-phenyl)-4-(1-methoxymethyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one

[0674] Part A and B

[0675] 4-(5-Chloro-4-methoxy-2-methyl-phenyl)-3-nitro-1H-pyridin-2-one was prepared substantially as described in Example 452.

[0676] Part C

[0677] Trifluoro-methanesulfonic acid 4-(5-chloro-4-methoxy-2-methyl-phenyl)-3-nitro-pyridin-2-yl ester (0.38 g, 0.89 mmol) and 1-methoxymethyl-propylamine (0.23 g, 2.23 mmol) were treated substantially as described in Part C of Example 19a to produce 0.13 g (40%) of crude [4-(5-chloro-4-methoxy-2-methyl-phenyl)-3-nitro-pyridin-2-yl]-(1-methoxymethyl-propyl)-amine: MS (EI) m/z 380.19 [(M+H)⁺, 100].

[0678] Part D

[0679] [4-(5-Chloro-4-methoxy-2-methyl-phenyl)-3-nitro-pyridin-2-yl]-(1-methoxymethyl-propyl)-amine (0.13 g, 0.34 mmol) and SnCl₂ (0.19 g, 1.03 mmol) were treated substantially as described in Part D of Example 74a to yield 0.12 g (99%) of (S)-4-(2-chloro-5-fluoro-4-methoxy-phenyl)-N²-(1-cyclopropyl-propyl)-pyridine-2,3-diamine: MS (EI) m/z 350.25 [(M+H)⁺, 100].

[0680] Part E

[0681] 4-(5-Chloro-4-methoxy-2-methyl-phenyl)-N²-(1-methoxymethyl-propyl)-pyridine-2,3-diamine (0.11 g, 0.32 mmol) was treated substantially as described in Part F of Example 9 to give 48 mg (38%) of 8-(5-chloro-4-methoxy-2-methyl-phenyl)-4-(1-methoxymethyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (Example 459): ¹H NMR (400 MHz, CDCl₃) δ ppm 8.50 (d, J=4.89 Hz, 1 H), 7.24 (s, 1 H), 7.12 (d, J=4.89 Hz, 1 H), 6.86 (s, 1 H), 5.89 (m, 1 H), 4.38 (m, 1 H), 3.96 (s, 3 H), 3.81 (m, 1 H), 3.32 (s, 3 H), 2.47 (s, 3 H), 2.29 (m, 1 H), 2.09 (s, 3 H), 1.98 (m, 1 H), 0.85 (t, J=7.46 Hz, 3 H). MS (EI) m/z 402.20 [(M+H)+, 100].

Example 484 8-(2-Chloro-4-methoxy-5-methyl-phenyl)-4-(1-cyclopropyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one

[0682] Part A

[0683] 2-Benzyloxy-4-chloro-3-nitro-pyridine (Wilde, et. al. WO 99/01454) (924 mg, 3.49 mmol) and 2-chloro-5-methyl-4-methoxyphenylboronic acid (prepared substantially as described in Speicher, A.; Kolz, J.; Sambanje, R. P. Synthesis, 2002, 17, 2503) (770 mg, 3.84 mmol) were treated substantially as described in Part A of Example 19a to give 514 mg (39%) of 2-benzyloxy-4-(2-chloro-4-methoxy-5-methyl-phenyl)-3-nitro-pyridine: ¹H NMR (400 MHz, CDCl₃) δ ppm 8.27 (d, J=5.4 Hz, 1 H), 7.47-7.44 (m, 2H), 7.40-7.30 (m, 3H), 7.00 (s, 1H), 6.94 (d, J=5.4 Hz, 1 H), 6.90 (s, 1 H), 5.55 (s, 2 H), 3.84 (s, 3 H), 2.17 (s, 3 H),

[0684] Part B

[0685] 2-Benzyloxy-4-(2-chloro-4-methoxy-5-methyl-phenyl)-3-nitro-pyridine (0.5 g, 1.30 mmol) was treated substantially as described in Part B of Example 19a to give 4-(2-chloro-4-methoxy-5-methyl-phenyl)-3-nitro-1H-pyridin-2-one (0.38 g, 100%): MS (EI) m/z 295.11 [(M+H)⁺, 100].

[0686] Part C

[0687] Trifluoro-methanesulfonic acid 4-(2-chloro-4-methoxy-5-methyl-phenyl)-3-nitro-pyridin-2-yl ester (0.22 g, 0.51 mmol), prepared substantially as described in Part C of Example 19a, and 1-cyclopropyl-propylamine (0.17 g, 1.29 mmol) were treated substantially as described in Part C of Example 19a to produce 90 mg (47%) of crude [4-(2-chloro-4-methoxy-5-methyl-phenyl)-3-nitro-pyridin-2-yl]-(1-cyclopropyl-propyl)-amine: MS (EI) m/z 376.18 [(M+H)⁺, 100].

[0688] Part D

[0689] [4-(2-Chloro-4-methoxy-5-methyl-phenyl)-3-nitro-pyridin-2-yl]-(1-cyclopropyl-propyl)-amine (90 mg, 0.24 mmol) and SnCl₂ (0.13 g, 0.72 mmol) were treated substantially as described in Part D of Example 74a to yield 80 mg (98%) of 4-(2-chloro-4-methoxy-5-methyl-phenyl)-N²-(1-cyclopropyl-propyl)-pyridine-2,3-diamine: MS (EI) m/z 346.22 [(M+H)⁺, 100].

[0690] Part E

[0691] 4-(2-Chloro-4-methoxy-5-methyl-phenyl)-N²-(1-cyclopropyl-propyl)-pyridine-2,3-diamine (80 mg, 0.23 mmol) was treated substantially as described in Part F of Example 9 to give 7.4 mg (8%) of 8-(2-Chloro-4-methoxy-5-methyl-phenyl)-4-(1-cyclopropyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (Example 484): ¹H NMR (400 MHz, CDCl₃) δ ppm 8.42 (d, J=4.89 Hz, 1 H), 7.17 (d, J=4.89 Hz, 1 H), 7.11 (s, 1 H), 6.95 (s, 1 H), 4.74 (m, 1 H), 3.91 (m, 3 H), 2.51 (m, 3 H), 2.34 (m, 1 H), 2.22 (m, 3 H), 2.08 (m, 1 H), 0.89 (m, 1 H), 0.86 (s, 3 H), 0.70 (m, 1 H), 0.46 (m, 1 H), 0.32 (m, 1 H), 0.17 (m, 1 H), MS (EI) m/z 398.23 [(M+H)+, 100].

Example 491 8-(2-Chloro-4-methoxy-5-methyl-phenyl)-4-(1-methoxymethyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one

[0692] Part A and B

[0693] 4-(2-Chloro-4-methoxy-5-methyl-phenyl)-3-nitro-1H-pyridin-2-one was prepared substantially as described in Example 484.

[0694] Part C

[0695] Trifluoro-methanesulfonic acid 4-(2-chloro-4-methoxy-5-methyl-phenyl)-3-nitro-pyridin-2-yl ester (0.22 g, 0.51 mmol) and 1-methoxymethyl-propylamine (0.13 g, 1.29 mmol) were treated substantially as described in Part C of Example 19a to produce 92 mg (47%) of crude [4-(5-chloro-4-methoxy-2-methyl-phenyl)-3-nitro-pyridin-2-yl]-(1-methoxymethyl-propyl)-amine: MS (EI) m/z 380.24 [(M+H)⁺, 100].

[0696] Part D

[0697] [4-(5-Chloro-4-methoxy-2-methyl-phenyl)-3-nitro-pyridin-2-yl]-(1-methoxymethyl-propyl)-amine (90 mg, 0.24 mmol) and SnCl₂ (0.13 g, 0.71 mmol) were treated substantially as described in Part D of Example 74a to yield 82 mg (99%) of 4-(2-Chloro-4-methoxy-5-methyl-phenyl)-N²-(1-methoxymethyl-propyl)-pyridine-2,3-diamine: MS (EI) m/z 350.23 [(M+H)⁺, 100].

[0698] Part E

[0699] 4-(2-Chloro-4-methoxy-5-methyl-phenyl)-N²-(1-methoxymethyl-propyl)-pyridine-2,3-diamine (82 mg, 0.22 mmol) was treated substantially as described in Part F of Example 9 to give 17.5 mg (19%) of 8-(2-chloro-4-methoxy-5-methyl-phenyl)-4-(1-methoxymethyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (Example 491): ¹H NMR (400 MHz, CDCl₃) δ ppm 8.51 (d, J=4.89 Hz, 1 H), 7.20 (d, J=4.89 Hz, 1 H), 7.09 (s, 1 H), 6.95 (s, 1 H), 5.89 (m, 1 H), 4.38 (m, 2 H), 3.88 (s, 3 H), 3.33 (m, 3 H), 2.48 (s, 3 H), 2.21 (s, 3 H), 2.09 (m, 2 H), 0.86 (t, J=7.46 Hz, 3 H). MS (EI) m/z 402.20 [(M+H)+, 100].

Example 500 8-(2-Chloro-4-dimethylamino-5-fluoro-phenyl)-4-(1-cyclopropyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one

[0700] Part A and B

[0701] 4-(2-Chloro-4-dimethylamino-5-fluoro-phenyl)-3-nitro-1H-pyridin-2-one was prepared substantially as described in Example 507.

[0702] Part C

[0703] Trifluoro-methanesulfonic acid 4-(2-chloro-4-dimethylamino-5-fluoro-phenyl)-3-nitro-pyridin-2-yl ester (548 mg, 1.76 mmol) and 1-cyclopropyl-propylamine HCl (479 mg, 3.5 mmol) were treated substantially as described in Part C of Example 19a to produce 300 mg (43%) of crude [4-(2-chloro-4-dimethylamino-5-fluoro-phenyl)-3-nitro-pyridin-2-yl]-(1-cyclopropyl-propyl)-amine: MS (EI) m/z 393.22 [(M+H)⁺, 100].

[0704] Part D

[0705] [4-(2-Chloro-4-dimethylamino-5-fluoro-phenyl)-3-nitro-pyridin-2-yl]-(1-cyclopropyl-propyl)-amine (300 mg, 0.76 mmol) and SnCl₂.H₂O (1.2 g, 6.1 mmol) were treated substantially as described in Part D of Example 74a to yield 276 mg of crude 4-(2-chloro-4-dimethylamino-5-fluoro-phenyl)-N²-(1-cyclopropyl-propyl)-pyridine-2,3-diamine: MS (EI) m/z 363.24 [(M+H)⁺, 100].

[0706] Part E

[0707] 4-(2-Chloro-4-dimethylamino-5-fluoro-phenyl)-N²-(1-cyclopropyl-propyl)-pyridine-2,3-diamine (299 mg, 0.76 mmol) was treated substantially as described in Part F of Example 9 to give 20 mg (6% for 4 steps) of 8-(2-chloro-4-dimethylamino-5-fluoro-phenyl)-4-(1-cyclopropyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (Example 500): ¹H NMR (400 MHz, CDCl₃) δ ppm 8.52 (d, J=4.65 Hz, 1 H), 7.60 (d, J=7.09 Hz, 1 H), 7.27 (m, 1 H), 7.19 (d, J=4.65 Hz, 1 H), 5.01 (m, 1 H), 3.26 (s, 6 H), 2.51 (s, 3 H), 2.25 (m, 2 H), 0.86 (t, J=7.34 Hz, 3 H), 0.73 (m, 1 H), 0.48 (m, 1 H), 0.34 (m, 1 H), 0.21 (m, 1 H), 0.13 (m, 1 H). MS (EI) m/z 415.26 [(M+H)+, 100].

Example 501a (R)-8-(2-Chloro-4-dimethylamino-5-fluoro-phenyl)-4-(1-cyclopropyl-ethyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one

[0708] Part A and B

[0709] 4-(2-Chloro-4-dimethylamino-5-fluoro-phenyl)-3-nitro-1H-pyridin-2-one was prepared substantially as described in Example 507.

[0710] Part C

[0711] Trifluoro-methanesulfonic acid 4-(2-chloro-4-dimethylamino-5-fluoro-phenyl)-3-nitro-pyridin-2-yl ester TFA (1.06 g, 2.49 mmol) and (R)-1-cyclopropyl-ethylamine HCl (202 mg, 1.7 mmol) were treated substantially as described in Part C of Example 19a to produce 314 mg of crude (R)-[4-(2-chloro-4-dimethylamino-5-fluoro-phenyl)-3-nitro-pyridin-2-yl]-(1-cyclopropyl-ethyl)-amine.

[0712] Part D

[0713] (R)-[4-(2-Chloro-4-dimethylamino-5-fluoro-phenyl)-3-nitro-pyridin-2-yl]-(1-cyclopropyl-ethyl)-amine (314 mg, 0.83 mmol) and SnCl₂.H₂O (472 mg, 2.5 mmol) were treated substantially as described in Part D of Example 74a to yield 276 mg of crude (R)-4-(2-chloro-4-dimethylamino-5-fluoro-phenyl)-N²-(1-cyclopropyl-ethyl)-pyridine-2,3-diamine: MS (EI) m/z 349.24 [(M+H)⁺, 100].

[0714] Part E

[0715] (R)-4-(2-Chloro-4-dimethylamino-5-fluoro-phenyl)-N²-(1-cyclopropyl-ethyl)-pyridine-2,3-diamine (290 mg, 0.83 mmol) was treated substantially as described in Part F of Example 9 to give 22.5 mg (8% for 4 steps) of (R)-8-(2-chloro-4-dimethylamino-5-fluoro-phenyl)-4-(1-cyclopropyl-ethyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (Example 501a): ¹H NMR (400 MHz, CDCl₃) δ ppm 8.47 (d, J=4.65 Hz, 1 H), 7.20 (d, J=4.65 Hz, 1 H), 7.14 (d, J=8.07 Hz, 1 H), 7.08 (d, J=12.96 Hz, 1 H), 4.85 (m, 1 H), 3.02 (s, 6 H), 2.50 (s, 3 H), 1.25 (s, 3 H), 0.87 (m, 1 H), 0.67 (m, 1 H), 0.42 (m, 2 H), 0.22 (m, 1 H). MS (EI) m/z 401.20 [(M+H)+, 100].

Example 503a (R)-8-(2-Chloro-4-dimethylamino-5-fluoro-phenyl)-4-(1-cyclobutyl-ethyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one

[0716] Part A and B

[0717] 4-(2-Chloro-4-dimethylamino-5-fluoro-phenyl)-3-nitro-1H-pyridin-2-one was prepared substantially as described in Example 507.

[0718] Part C

[0719] Trifluoro-methanesulfonic acid 4-(2-chloro-4-dimethylamino-5-fluoro-phenyl)-3-nitro-pyridin-2-yl ester TFA (1.1 g, 2.49 mmol) and (R)-1-cyclobutyl-ethylamine HCl (225 mg, 1.7 mmol) were treated substantially as described in Part C of Example 19a to produce 326 mg of crude (R)-[4-(2-Chloro-4-dimethylamino-5-fluoro-phenyl)-3-nitro-pyridin-2-yl]-(1-cyclobutyl-ethyl)-amine.

[0720] Part D

[0721] (R)-[4-(2-Chloro-4-dimethylamino-5-fluoro-phenyl)-3-nitro-pyridin-2-yl]-(1-cyclobutyl-ethyl)-amine (326 mg, 0.83 mmol) and SnCl₂.H₂O (472 mg, 2.5 mmol) were treated substantially as described in Part D of Example 74a to yield 301 mg of crude (R)-4-(2-Chloro-4-dimethylamino-5-fluoro-phenyl)-N²-(1-cyclobutyl-ethyl)-pyridine-2,3-diamine: MS (EI) m/z 363.24 [(M+H)⁺, 100].

[0722] Part E

[0723] (R)-4-(2-Chloro-4-dimethylamino-5-fluoro-phenyl)-N²-(1-cyclobutyl-ethyl)-pyridine-2,3-diamine (301 mg, 0.83 mmol) was treated substantially as described in Part F of Example 9 to give 8.5 mg (3% for 4 steps) of (R)-8-(2-Chloro-4-dimethylamino-5-fluoro-phenyl)-4-(1-cyclobutyl-ethyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (Example 503a): ¹H NMR (400 MHz, CDCl₃) δ ppm 8.52 (br s, 1 H), 7.17 (br s, 1 H), 7.04 (d, J=13.20 Hz, 1 H), 6.99 (d, J=8.07 Hz, 1 H), 5.70 (d, 1 H), 2.96 (s, 6 H), 2.49 (m, 3 H), 1.79 (m, 4 H), 1.51 (m, 2 H), H), 1.28 (m, 1 H), 1.25 (s, 3 H). MS (EI) m/z 415.24 [(M+H)+, 100].

Example 506 8-(2-Chloro-4-dimethylamino-5-fluoro-phenyl)-4-(2-methoxy-1-methyl-ethyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one

[0724] Part A and B

[0725] 4-(2-Chloro-4-dimethylamino-5-fluoro-phenyl)-3-nitro-1H-pyridin-2-one was prepared substantially as described in Example 507.

[0726] Part C

[0727] Trifluoro-methanesulfonic acid 4-(2-chloro-4-dimethylamino-5-fluoro-phenyl)-3-nitro-pyridin-2-yl ester TFA (1.1 g, 2.49 mmol) and 2-methoxy-1-methyl-ethylamine HCl (208 mg, 1.7 mmol) were treated substantially as described in Part C of Example 19a to produce 318 mg of crude [4-(2-chloro-4-dimethylamino-5-fluoro-phenyl)-3-nitro-pyridin-2-yl]-(2-methoxy-1-methyl-ethyl)-amine.

[0728] Part D

[0729] [4-(2-Chloro-4-dimethylamino-5-fluoro-phenyl)-3-nitro-pyridin-2-yl]-(2-methoxy-1-methyl-ethyl)-amine (318 mg, 0.83 mmol) and SnCl₂.H₂O (472 mg, 2.5 mmol) were treated substantially as described in Part D of Example 74a to yield 290 mg of crude 4-(2-chloro-4-dimethylamino-5-fluoro-phenyl)-N²-(2-methoxy-1-methyl-ethyl)-pyridine-2,3-diamine: MS (EI) m/z 353.23 [(M+H)⁺, 100].

[0730] Part E

[0731] 4-(2-Chloro-4-dimethylamino-5-fluoro-phenyl)-N²-(2-methoxy-1-methyl-ethyl)-pyridine-2,3-diamine (290 mg, 0.83 mmol) was treated substantially as described in Part F of Example 9 to give 22.5 mg (8% for 4 steps) of 8-(2-chloro-4-dimethylamino-5-fluoro-phenyl)-4-(2-methoxy-1-methyl-ethyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (Example 506): ¹H NMR (400 MHz, CDCl₃) δ ppm 8.53 (d, J=4.65 Hz, 1 H), 7.26 (d, J=7.58 Hz, 1 H), 7.20 (d, J=4.65 Hz, 1 H), 7.11 (d, J=12.72 Hz, 1 H), 5.88 (m, 1 H), 4.39 (m, 1 H), 3.79 (m, 1 H), 3.34 (s, 3 H), 3.08 (s, 6 H), 2.49 (s, 3 H), 1.60 (d, J=6.85 Hz, 3 H). MS (EI) m/z 405.23 [(M+H)+, 100].

Example 507 8-(2-Chloro-4-dimethylamino-5-fluoro-phenyl)-4-(1-methoxymethyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one

[0732] Part A

[0733] 2-Benzyloxy-4-chloro-3-nitro-pyridine (Wilde, et. al. WO 99/01454) (800 mg, 3.02 mmol) and 2-chloro-4-dimethylamino-5-fluorophenylboronic acid (Example B) (854 mg, 3.93 mmol) were treated substantially as described in Part A of Example 19a to give 715 mg (59%) of 2-benzyloxy-4-(2-chloro-4-dimethylamino-5-fluoro-phenyl)-3-nitro-pyridine: ¹H NMR (400 MHz, CDCl₃) δ ppm 8.27 (d, J=5.4 Hz, 1 H), 7.45-7.43 (m, 2H), 7.40-7.29 (m, 3H), 6.93 (d, J=5.4 Hz, 1 H), 6.89 (d, J=13.2 Hz, 1 H), 6.85 (d, J=8.0 Hz, 1 H), 5.53 (s, 2 H), 2.91 (d, J=1.2 Hz, 6 H).

[0734] Part B

[0735] 2-Benzyloxy-4-(2-chloro-4-dimethylamino-5-fluoro-phenyl)-3-nitro-pyridine (2.8 g, 7.0 mmol) was treated substantially as described in Part B of Example 19a to give 4-(2-chloro-4-dimethylamino-5-fluoro-phenyl)-3-nitro-1H-pyridin-2-one TFA (3.0 g, 100%): ¹H NMR (400 MHz, CDCl₃) δ ppm 7.59 (d, J=6.7 Hz, 1 H), 6.99 (d, J=7.8 Hz, 1 H), 6.96 (d, J=12.7 Hz, 1 H), 6.54 (d, J=6.7 Hz, 1 H), 2.99 (d, J=1.2 Hz, 6 H).

[0736] Part C

[0737] Trifluoro-methanesulfonic acid 4-(2-chloro-4-dimethylamino-5-fluoro-phenyl)-3-nitro-pyridin-2-yl ester TFA (39.6 mg, 0.093 mmol), prepared substantially as described in Part C of Example 19a, and 1-methoxymethyl-propylamine (191.0 mg, 1.85 mmol) were treated substantially as described in Part C of Example 19a to produce 30 mg (81%) of crude [4-(2-chloro-4-dimethylamino-5-fluoro-phenyl)-3-nitro-pyridin-2-yl]-(1-methoxymethyl-propyl)-amine: MS (EI) m/z 397.19 [(M+H)⁺, 100].

[0738] Part D

[0739] [4-(2-Chloro-4-dimethylamino-5-fluoro-phenyl)-3-nitro-pyridin-2-yl]-(1-methoxymethyl-propyl)-amine (30.0 mg, 0.076 mmol) and SnCl₂.H₂O (43.2 mg, 0.23 mmol) were treated substantially as described in Part D of Example 74a to yield 30 mg (100% crude) of 4-(2-Chloro-4-dimethylamino-5-fluoro-phenyl)-N²-(1-methoxymethyl-propyl)-pyridine-2,3-diamine: MS (EI) m/z 367.23 [(M+H)⁺, 100].

[0740] Part E

[0741] 4-(2-Chloro-4-dimethylamino-5-fluoro-phenyl)-N²-(1-methoxymethyl-propyl)-pyridine-2,3-diamine (27.9 mg, 0.076 mmol) was treated substantially as described in Part F of Example 9 to give 4 mg of 8-(2-Chloro-4-dimethylamino-5-fluoro-phenyl)-4-(1-methoxymethyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (Example 507): ¹H NMR (400 MHz, CDCl₃) δ ppm 8.55 (d, J=4.16 Hz, 1 H), 7.20 (d, J=4.16 Hz, 1 H), 7.10 (d, J=6.11 Hz, 1 H), 7.07 (d, J=11.49 Hz, 1 H), 6.15 (m, 1 H), 4.38 (m, 1 H), 3.81 (m, 1 H), 3.32 (m, 3 H), 3.01 (m, 6 H), 2.49 (s, 3 H), 2.11 (m, 2 H), 0.86 (t, J=7.46 Hz, 3 H). MS (EI) m/z 419.25 [(M+H)+, 100].

Example 546 (R,S)-8-sec-Butyl-4-(2,4-dichloro-phenyl)-6-methyl-8H-pteridin-7-one

[0742] Part A

[0743] 4,6-Dichloro-5-nitropyrimidine (2.0 g, 0.012 mol) was diluted in EtOH (10 ml) and toluene (40 ml). A 2M Na₂CO₃ (15.0 ml) was added followed by Pd(PPh₃)₂Cl₂ (0.51 g, 0.0007 mol), and 2,4-dichlorophenylboronic acid (0.018 mol). The reaction was warmed to reflux under an inert atmosphere for 5 hours. The reaction was then allowed to cool to room temperature and poured over EtOAc/H₂O. The organic layer was separated and washed with sat'd sodium chloride, dried (MgSO₄), filtered and concentrated. The material was flushed through a plug of silica using 50% EtOAc/hexane as an eluting solvent. The crude material (2.9 g) was concentrated in vacuo and diluted in 20 ml butanol. Sec-butylamine was added to the solution and the mixture warmed to reflux for 18 hours. After concentrating the solution in vacuo and purification on silica gel using 80% EtOAc/hexane as the eluting solvent the desired intermediate N⁴-sec-butyl-6-(2,4-dichloro-phenyl)-pyrimidine-4,5-diamine was isolated (1.49 g, 40%). MS (AP) m/z 311.1 [(M+H)⁺, 100].

[0744] Part B

[0745] N⁴-sec-butyl-6-(2,4-dichloro-phenyl)-pyrimidine-4,5-diamine (0.10 g, 0.00032 mol) was diluted in ethanol (20 ml) and ethyl pyruvate was added (0.68 ml, 0.006 mol). The mixture was stirred for 18 hours at which time 10 ml of the solution was removed and concentrated. The residue was diluted in glacial acetic acid (10 ml) and warmed to 100 C for 1 hour. After concentrating the solution the product was purified by reverse phase HPLC to yield 9.8 mg of (R,S)-8-sec-butyl-4-(2,4-dichloro-phenyl)-6-methyl-8H-pteridin-7-one (Example 546). ¹H NMR (300 MHz, CD₃OD) δ 9.02 (s, 1H), 7.66-7.64 (d, 1H), 7.49-7.48 (m, 2H), 5.68 (m, 1H), 2.42 (s, 3H), 2.39-2.25 (m, 1H), 2.01-2.15 (m, 1H), 1.64-1.62 (d, 3H), 0.89-0.84 (t, 3H). MS (AP) 363.1 [(M+H)+, 100], 404.1 [(M+H+ACN)+, 20].

Example 563 4-(2-Chloro-4-methoxy-phenyl)-6-methyl-8-(1-propyl-butyl)-8H-pteridin-7-one

[0746] Part A

[0747] 4,6-Dichloro-5-aminopyrimidine (5.8 g, 0.036 mol) was diluted in EtOH (25 ml) and toluene (100 ml). A 2M Na₂CO₃ (45.0 ml) was added followed by Pd(PPh₃)₂Cl₂ (1.5 g, 0.0021 mol), and 2-chloro-4-methoxyphenylboronic acid (0.035 mol). The reaction was warmed to reflux under an inert atmosphere for 5 hours. The reaction was then allowed to cool to room temperature and poured over EtOAc/H₂O. The organic layer was separated and washed with sat'd sodium chloride, dried (MgSO₄), filtered and concentrated. The material was flushed through a plug of silica using 50% EtOAc/hexane as an eluting solvent. The crude material was concentrated in vacuo and diluted in 5 ml butanol. 4-Heptyamine was added to the solution and the mixture warmed to reflux for 18 hours. After concentrating the solution in vacuo and purification on silica gel using 80% EtOAc/hexane as the eluting solvent the desired intermediate 6-(2-chloro-4-methoxy-phenyl)-N4-(1-propyl-butyl)-pyrimidine-4,5-diamine was isolated (0.29 g, 73%). MS (AP) 349.3 [(M+H)+, 100].

[0748] Part B

[0749] 6-(2-Chloro-4-methoxy-phenyl)-N4-(1-propyl-butyl)-pyrimidine-4,5-diamine (0.29 g, 0.83 mmol) was diluted in ethanol (8 ml) and ethyl pyruvate was added (0.92 ml, 8.3 mmol). The mixture was stirred for 18 hours at which time the solution was concentrated. The residue was diluted in glacial acetic acid (10 ml) and warmed to 100° C. for 1 hour. After concentrating the solution the product was purified by reverse phase HPLC to yield 13.5 mg of 4-(2-chloro-4-methoxy-phenyl)-6-methyl-8-(1-propyl-butyl)-8H-pteridin-7-one (Example 563). ¹H NMR (300 MHz, CDCl₃) δ ppm 9.02 (s, 1 H), 7.41 (d, J=8.42 Hz, 1 H), 7.05 (d, J=2.56 Hz, 1 H), 6.93 (dd, J=8.42, 2.56 Hz, 1 H), 3.86 (s, 3 H), 4.40 (m, 1H), 2.48 (m, 2 H), 2.31 (m, 2 H), 1.89 (m, 2 H), 1.19 (m, 5 H), 0.88 (t, J=7.32 Hz, 6 H). MS (AP) 321.2 [(M+H)+, 100]. MS (AP) 401.3 [(M+H)+, 100].

Example 565a (R)-4-(2-Chloro-4-methoxy-phenyl)-8-(1-cyclopropyl-ethyl)-6-methyl-8H-pteridin-7-one

[0750] Part A

[0751] 4-Chloro-6-(2-chloro-4-methoxy-phenyl)-pyrimidin-5-ylamine (prepared substantially as described in Example 466) (0.25 g, 0.93 mmol) was diluted in butanol (9 mL). (R)-1-Cyclopropyl-ethylamine (0.25 g, 2.05 mmol) and triethylamine (0.52 mL, 3.6 mmol) were added to the solution and the mixture warmed to reflux for 18 hours. After concentrating the solution in vacuo and purification on silica gel using 100% EtOAc/hexane as the eluting solvent the desired intermediate (R)-6-(2-chloro-4-methoxy-phenyl)-N4-(1-cyclopropyl-ethyl)-pyrimidine-4,5-diamine was isolated (0.17 g, 57%).

[0752] Part B

[0753] (R)-6-(2-Chloro-4-methoxy-phenyl)-N4-(1-cyclopropyl-ethyl)-pyrimidine-4,5-diamine (0.20 g, 0.52 mmol) was diluted in ethanol (5 ml) and ethyl pyruvate was added (0.58 ml, 5.2 mmol). The mixture was stirred for 18 hours at which time the solution was concentrated. The residue was diluted in glacial acetic acid (10 ml) and warmed to 100° C. for 1 hour. After concentrating the solution the product was purified by reverse phase HPLC to yield 2.0 mg of (R)-4-(2-chloro-4-methoxy-phenyl)-8-(1-cyclopropyl-ethyl)-6-methyl-8H-pteridin-7-one (Example 565a). ¹H NMR (300 MHz, CDCl₃) δ ppm 9.04 (s, 1 H), 7.45 (d, J=8.42 Hz, 1 H), 7.09 (d, J=2.56 Hz, 1 H), 6.98 (dd, J=8.42, 2.56 Hz, 1 H), 4.26 (m, 1 H), 3.91 (s, 3 H), 2.54 (d, J=7.32, 3 H), 2.18 (m, 3 H), 0.87 (m, 2 H), 0.45 (m, 2 H), 0.26 (m, 1 H). MS (AP) 371.3 [(M+H)+, 100].

Example 567a (S)-4-(2-Chloro-4-methoxy-phenyl)-8-(1-cyclobutyl-ethyl)-6-methyl-8H-pteridin-7-one

[0754] Part A

[0755] 4-Chloro-6-(2-chloro-4-methoxy-phenyl)-pyrimidin-5-ylamine (prepared substantially as described in Example 466) (0.23 g, 0.86 mmol) was diluted in butanol (9 mL). (S)-1-Cyclobutyl-ethylamine (0.25 g, 1.9 mmol) and triethylamine (0.48 mL, 3.4 mmol) were added to the solution and the mixture warmed to reflux for 18 hours. After concentrating the solution in vacuo and purification on silica gel using 100% EtOAc/hexane as the eluting solvent the desired intermediate (S)-6-(2-chloro-4-methoxy-phenyl)-N4-(1-cyclobutyl-ethyl)-pyrimidine-4,5-diamine was isolated (0.23 g, 81%). MS (AP) 333.3 [(M+H)+, 100].

[0756] Part B

[0757] (S)-6-(2-Chloro-4-methoxy-phenyl)-N4-(1-cyclobutyl-ethyl)-pyrimidine-4,5-diamine (0.23 g, 0.69 mmol) was diluted in ethanol (7 ml) and ethyl pyruvate was added (0.78 ml, 6.9 mmol). The mixture was stirred for 18 hours at which time the solution was concentrated. The residue was diluted in glacial acetic acid (10 ml) and warmed to 100° C. for 1 hour. After concentrating the solution the product was purified by reverse phase HPLC to yield 2.0 mg of (S)-4-(2-chloro-4-methoxy-phenyl)-8-(1-cyclobutyl-ethyl)-6-methyl-8H-pteridin-7-one (Example 567a). ¹H NMR (300 MHz, CDCl₃) δ ppm 9.06 (s, 1 H), 7.46 (d, J=8.79 Hz, 1 H), 7.09 (d, J=2.56 Hz, 1 H), 6.97 (dd, J=8.79, 2.56 Hz, 1 H), 5.82 (m, 1 H), 3.91 (s, 3 H), 2.51 (s, 3 H), 2.22 (m, 2 H), 1.87 (m, 4 H), 1.74 (s, 3 H), 1.55 (m, 1 H). MS (AP) 385.3 [(M+H)+, 100].

Example 570a (R)-4-(2-Chloro-4-methoxy-phenyl)-8-(2-methoxy-1-methyl-ethyl)-6-methyl-8H-pteridin-7-one

[0758] Part A

[0759] 4-Chloro-6-(2-chloro-4-methoxy-phenyl)-pyrimidin-5-ylamine (prepared substantially as described in Example 466) (0.28 g, 1.0 mmol) was diluted in butanol (10 mL). (R)-2-Methoxy-1-methyl-ethylamine (0.29 g, 3.3 mmol) and triethylamine (0.59 mL, 4.0 mmol) were added to the solution and the mixture warmed to reflux for 18 hours. After concentrating the solution in vacuo and purification on silica gel using 100% EtOAc/hexane as the eluting solvent the desired intermediate (R)-6-(2-chloro-4-methoxy-phenyl)-N4-(2-methoxy-1-methyl-ethyl)-pyrimidine-4,5-diamine (0.26 g, 85%). MS (AP) 321.2 [(M+H)+, 100].

[0760] Part B

[0761] (R)-6-(2-Chloro-4-methoxy-phenyl)-N4-(2-methoxy-1-methyl-ethyl)-pyrimidine-4,5-diamine (0.26 g, 0.82 mmol) was diluted in ethanol (8 ml) and ethyl pyruvate was added (0.92 ml, 8.2 mmol). The mixture was stirred for 18 hours at which time the solution was concentrated. The residue was diluted in glacial acetic acid (10 ml) and warmed to 100° C. for 1 hour. After concentrating the solution the product was purified by reverse phase HPLC to yield 6.0 mg of (R)-4-(2-chloro-4-methoxy-phenyl)-8-(2-methoxy-1-methyl-ethyl)-6-methyl-8H-pteridin-7-one (Example 570a). ¹H NMR (300 MHz, CDCl₃) δ ppm 9.09 (s, 1 H), 7.43 (d, J=8.79 Hz, 1 H), 7.09 (d, J=2.56 Hz, 1 H), 6.97 (dd, J=8.79, 2.56 Hz, 1 H), 4.39 (m, 3H), 3.91 (s, 3 H), 3.73 (dd, J=10.07, 5.31 Hz, 2 H), 3.35 (s, 3H), 2.53 (s, 3 H), 1.62 (6, J=6.96 Hz, 3 H). MS (AP) 375.2 [(M+H)+, 100].

Example 571a (R)-4-(2-Chloro-4-methoxy-phenyl)-8-(1-methoxymethyl-propyl)-6-methyl-8H-pteridin-7-one

[0762] Part A

[0763] 4-Chloro-6-(2-chloro-4-methoxy-phenyl)-pyrimidin-5-ylamine (prepared substantially as described in Example 466) (0.22 g, 0.81 mmol) was diluted in butanol (8 mL). (R)-2-Ethoxy-1-methyl-ethylamine (0.25 g, 1.8 mmol) and triethylamine (0.45 mL, 3.0 mmol) were added to the solution and the mixture warmed to reflux for 18 hours. After concentrating the solution in vacuo and purification on silica gel using 100% EtOAc/hexane as the eluting solvent the desired intermediate (R)-6-(2-chloro-4-methoxy-phenyl)-N4-(1-methoxymethyl-propyl)-pyrimidine-4,5-diamine (0.20 g, 74%). MS (AP) 337.2 [(M+H)+, 100].

[0764] Part B

[0765] (R)-6-(2-Chloro-4-methoxy-phenyl)-N4-(1-methoxymethyl-propyl)-pyrimidine-4,5-diamine (0.20 g, 0.60 mmol) was diluted in ethanol (6 ml) and ethyl pyruvate was added (0.68 ml, 6.0 mmol). The mixture was stirred for 18 hours at which time the solution was concentrated. The residue was diluted in glacial acetic acid (10 ml) and warmed to 100° C. for 1 hour. After concentrating the solution the product was purified by reverse phase HPLC to yield 5.0 mg of (R)-4-(2-chloro-4-methoxy-phenyl)-8-(1-methoxymethyl-propyl)-6-methyl-8H-pteridin-7-one (Example 571a). ¹H NMR (300 MHz, CDCl₃) δ ppm 9.02 (s, 1 H), 7.41 (d, J=8.79 Hz, 1 H), 7.05 (d, J=2.56 Hz, 1 H), 6.93 (dd, J=8.79, 2.56 Hz, 1 H), 3.87 (s, 3 H), 3.73 (m, 2 H), 3.29 (s, 3 H), 2.63 (m, 2H), 2.49 (s, 3 H), 2.10 (m, 2 H), 0.87 (t, J=7.51 Hz, 3 H). MS (AP) 389.3 [(M+H)+, 100].

Example 612a (R)-8-(1-Cyclopropyl-propyl)-4-(4-methoxy-2-methyl-phenyl)-6-methyl-8H-pteridin-7-one

[0766] Part A

[0767] 4,6-Dichloro-5-aminopyrimidine (2.0 g, 12.0 mmol) was diluted in EtOH (10 ml) and toluene (40 ml). A 2M Na₂CO₃ (15.0 ml) was added followed by Pd(PPh₃)₂Cl₂ (0.51 g, 0.72 mmol), and 4-methoxy-2-methylphenylboronic acid (2.0 g, 12.0 mmol). The reaction was warmed to reflux under an inert atmosphere for 5 hours. The reaction was then allowed to cool to room temperature and poured over EtOAc/H₂O. The organic layer was separated and washed with sat'd sodium chloride, dried (MgSO₄), filtered and concentrated. The material was flushed through a plug of silica using 50% EtOAc/hexane as an eluting solvent. The crude material was concentrated in vacuo and diluted in 10 mL butanol. (R)-1-Cyclopropyl-propylamine (0.29 g, 2.11 mmol) and triethylamine (0.45 mL, 3.0 mmol) was added to the solution and the mixture warmed to reflux for 18 hours. After concentrating the solution in vacuo and purification on silica gel using 80% EtOAc/hexane as the eluting solvent the desired intermediate (R)-N4-(1-Cyclopropyl-propyl)-6-(4-methoxy-2-methyl-phenyl)-pyrimidine-4,5-diamine was isolated (0.20 g, 68%).

[0768] Part B

[0769] (R)-N4-(1-Cyclopropyl-propyl)-6-(4-methoxy-2-methyl-phenyl)-pyrimidine-4,5-diamine (0.21 g, 0.67 mmol) was diluted in ethanol (7 ml) and ethyl pyruvate was added (0.75 ml, 6.7 mmol). The mixture was stirred for 18 hours at which time the solution was concentrated. After concentrating the solution the product was purified by reverse phase HPLC to yield 2.0 mg of (R)-8-(1-Cyclopropyl-propyl)-4-(4-methoxy-2-methyl-phenyl)-6-methyl-8H-pteridin-7-one (Example 612a). ¹H NMR (300 MHz, CDCl₃) δ ppm 8.86 (s, 1 H), 7.33 (d, J=9.15 Hz, 1 H), 6.80 (d, J=2.20 Hz, 1 H), 6.78 (d, J=2.20 Hz, 1 H), 4.56 (m, 1 H), 3.80 (s, 3 H), 2.45 (s, 3 H), 2.30 (m, 1 H), 2.20 (s, 3 H), 2.12 (m, 1 H), 0.81 (t, J=7.51 Hz, 3 H), 0.76 (m, 1 H), 0.68 (m, 1 H), 0.42 (m, 1 H), 0.29 (m, 1 H), 0.12 (m, 1 H). MS (EI) 377.3 [(M+H)+, 100].

Example 644a (R)-8-(1-Cyclopropyl-propyl)-4-(6-methoxy-2-methyl-pyridin-3-yl)-6-methyl-8H-pteridin-7-one

[0770] Part A

[0771] 4,6-Dichloro-5-aminopyrimidine (2.5 g, 15.0 mmol) was diluted in EtOH (10 ml) and toluene (40 ml). A 2M Na₂CO₃ (18.8 ml) was added followed by Pd(PPh₃)₂Cl₂ (0.63 g, 0.90 mmol), and 2-methoxy-6-methyl pyridine boronic acid (Wilde, et al. WO99/01454) (2.5 g, 15.0 mmol). The reaction was warmed to reflux under an inert atmosphere for 5 hours. The reaction was then allowed to cool to room temperature and poured over EtOAc/H₂O. The organic layer was separated and washed with sat'd sodium chloride, dried (MgSO₄), filtered and concentrated. The material was flushed through a plug of silica using 50% EtOAc/hexane as an eluting solvent. The crude material was concentrated in vacuo and diluted in 10 mL butanol. (R)-1-Cyclopropyl-propylamine (0.29 g, 2.11 mmol) and triethylamine (0.45 mL, 3.0 mmol) was added to the solution and the mixture warmed to reflux for 18 hours. After concentrating the solution in vacuo and purification on silica gel using 80% EtOAc/hexane as the eluting solvent the desired intermediate (R)-N4-(1-cyclopropyl-propyl)-6-(6-methoxy-2-methyl-pyridin-3-yl)-pyrimidine-4,5-diamine was isolated (0.20 g, 68%). MS (AP) 314.3 [(M+H)+, 100].

[0772] Part B

[0773] (R)-N4-(1-Cyclopropyl-propyl)-6-(6-methoxy-2-methyl-pyridin-3-yl)-pyrimidine-4,5-diamine (0.20 g, 0.64 mmol) was diluted in ethanol (7 ml) and ethyl pyruvate was added (0.73 ml, 6.4 mmol). The mixture was stirred for 18 hours at which time the solution was concentrated. After concentrating the solution the product was purified by reverse phase HPLC to yield 2.0 mg of (R)-8-(1-cyclopropyl-propyl)-4-(6-methoxy-2-methyl-pyridin-3-yl)-6-methyl-8H-pteridin-7-one (Example 644a). ¹H NMR (300 MHz, CDCl₃) δ ppm 8.92 (s, 1 H), 7.68 (d, J=8.05 Hz, 1 H), 6.68 (d, J=9.15 Hz, 1 H), 4.84 (m, 1 H), 3.99 (s, 3 H),), 2.51 (s, 3 H), 2.39 (s, 3 H), 1.20 (m, 2 H), 0.86 (m, 8 H). MS (EI) 366.3 [(M+H)+, 100].

Example 650a (R)-8-(2-Methoxy-1-methyl-ethyl)-4-(6-methoxy-2-methyl-pyridin-3-yl)-6-methyl-8H-pteridin-7-one

[0774] Part A

[0775] 6-(6-Methoxy-2-methyl-pyridin-3-yl)-pyrimidine-4,5-diamine (prepared substantially as described in Example 644a) (0.25 g, 1.0 mmol) was diluted in 10 mL butanol. (R)-2-Methoxy-1-methyl-ethylamine (0.28 g, 2.2 mmol) and triethylamine (0.56 mL, 4.0 mmol) was added to the solution and the mixture warmed to reflux for 18 hours. After concentrating the solution in vacuo and purification on silica gel using 100% EtOAc/hexane as the eluting solvent the desired intermediate (R)-N4-(2-methoxy-1-methyl-ethyl)-6-(6-methoxy-2-methyl-pyridin-3-yl)-pyrimidine-4,5-diamine was isolated (0.22 g, 74%).

[0776] Part B

[0777] (R)-N4-(2-Methoxy-1-methyl-ethyl)-6-(6-methoxy-2-methyl-pyridin-3-yl)-pyrimidine-4,5-diamine (0.22 g, 0.74 mmol) was diluted in ethanol (8 ml) and ethyl pyruvate was added (0.82 ml, 7.4 mmol). The mixture was stirred for 18 hours at which time the solution was concentrated. After concentrating the solution the product was purified by preparative TLC eluting with 35% ethyl acetate in hexanes to yield 5.0 mg of (R)-8-(2-methoxy-1-methyl-ethyl)-4-(6-methoxy-2-methyl-pyridin-3-yl)-6-methyl-8H-pteridin-7-one (Example 650a). ¹H NMR (300 MHz, CDCl₃) δ ppm 8.99 (s, 1 H), 7.65 (d, J=8.42 Hz, 1 H), 6.68 (d, J=8.42 Hz, 1 H), 5.71 (m, 1H), 3.99 (s, 3 H), 3.59 (m, 2 H), 3.31 (s, 3 H), 2.50 (s, 3H), 2.50 (s, 3H), 2.50 (s, 3H), 0.85 (d, J=7.69 Hz, 3 H). MS (EI) 356.3 [(M+H)+, 100].

Example 651a (R)-8-(1-Methoxymethyl-propyl)-4-(6-methoxy-2-methyl-pyridin-3-yl)-6-methyl-8H-pteridin-7-one

[0778] Part A

[0779] 6-(6-Methoxy-2-methyl-pyridin-3-yl)-pyrimidine-4,5-diamine (prepared substantially as described in Example 644a) (0.21 g, 0.84 mmol) was diluted in 10 mL butanol. (R)-2-Methoxy-1-methyl-ethylamine (0.26 g, 1.8 mmol) and triethylamine (0.47 mL, 3.4 mmol) was added to the solution and the mixture warmed to reflux for 18 hours. After concentrating the solution in vacuo and purification on silica gel using 100% EtOAc/hexane as the eluting solvent the desired intermediate (R)-N4-(1-methoxymethyl-propyl)-6-(6-methoxy-2-methyl-pyridin-3-yl)-pyrimidine-4,5-diamine was isolated (0.20 g, 75%). MS (AP) 318.3 [(M+H)+, 100].

[0780] Part B

[0781] (R)-N4-(1-Methoxymethyl-propyl)-6-(6-methoxy-2-methyl-pyridin-3-yl)-pyrimidine-4,5-diamine (0.2 g, 0.63 mmol) was diluted in ethanol (7 ml) and ethyl pyruvate was added (0.70 ml, 6.3 mmol). The mixture was stirred for 18 hours at which time the solution was concentrated. After concentrating the solution the product was purified by reverse phase HPLC to yield 4.0 mg of (R)-8-(1-methoxymethyl-propyl)-4-(6-methoxy-2-methyl-pyridin-3-yl)-6-methyl-8H-pteridin-7-one (Example 651a). ¹H NMR (300 MHz, CDCl₃) δ ppm 8.93 (s, 1 H), 7.62 (d, J=8.42 Hz, 1 H), 6.64 (d, J=8.42 Hz, 1 H), 4.23 (m, 1H), 3.94 (s, 3 H), 3.68 (m, 2 H), 3.25 (s, 3 H), 2.45 (s, 3H), 2.34 (s, 3 H), 1.22 (m, 2H), 0.82 (t, J=7.51 Hz, 3 H). MS (EI) 370.3 [(M+H)+, 100].

Example 1013a (R)-4-(4-Methoxy-2,5-dimethyl-phenyl)-8-(1-methoxymethyl-propyl)-6-methyl-8H-pteridin-7-one

[0782] Part A

[0783] 4,6-Dichloro-5-aminopyrimidine (0.91 g, 5.6 mmol) was diluted in EtOH (5 ml) and toluene (20 ml). A 2M Na₂CO₃ (6.9 ml) was added followed by Pd(PPh₃)₂Cl₂ (0.23 g, 0.34 mmol), and 4-methoxy-2,5-dimethylphenylboronic acid (Wilde, et al. WO99/01454)(1.0 g, 5.6 mmol). The reaction was warmed to reflux under an inert atmosphere for 5 hours. The reaction was then allowed to cool to room temperature and poured over EtOAc/H₂O. The organic layer was separated and washed with sat'd sodium chloride, dried (MgSO₄), filtered and concentrated. The material was flushed through a plug of silica using 100% EtOAc/hexane as an eluting solvent. The crude material was concentrated in vacuo and diluted in 10 mL butanol. (R)-1-Cyclopropyl-propylamine (0.21 g, 0.82 mmol) and triethylamine (0.46 mL, 3.3 mmol) was added to the solution and the mixture warmed to reflux for 18 hours. After concentrating the solution in vacuo and purification on silica gel using 100% EtOAc/hexane as the eluting solvent the desired intermediate (R)-6-(4-methoxy-2,5-dimethyl-phenyl)-N4-(1-methoxymethyl-propyl)-pyrimidine-4,5-diamine was isolated (0.22 g, 82%).

[0784] Part B

[0785] (R)-6-(4-Methoxy-2,5-dimethyl-phenyl)-N4-(1-methoxymethyl-propyl)-pyrimidine-4,5-diamine (0.22 g, 0.68 mmol) was diluted in ethanol (7 ml) and ethyl pyruvate was added (0.76 ml, 6.8 mmol). The mixture was stirred for 18 hours at which time the solution was concentrated. After concentrating the solution the product was purified by reverse phase HPLC to yield 8.0 mg of (R)-4-(4-methoxy-2,5-dimethyl-phenyl)-8-(1-methoxymethyl-propyl)-6-methyl-8H-pteridin-7-one (Example 1013a). ¹H NMR (300 MHz, CDCl₃) δ ppm 9.05 (s, 1 H), 7.21 (s, 1 H), 6.79 (s, 1 H), 4.86 (m, 1 H), 3.91 (s, 3 H), 2.55 (m, 3 H), 2.38 (m, 1 H), 2.22 (s, 3 H),), 2.22 (s, 3 H), 2.04 (m, 1 H), 1.25 (m, 1 H), 0.89 (t, J=7.51 Hz, 3 H), 0.77 (m, 1 H), 0.50 (m, 1 H), 0.39 (m, 1 H), 0.18 (m, 1 H). MS (EI) 379.3 [(M+H)+, 100].

Example 1061a (R)-4-(2-Chloro-4-trifluoromethoxy-phenyl)-8-(1-cyclopropyl-propyl)-6-methyl-8H-pteridin-7-one

[0786] Part A

[0787] 4,6-Dichloro-5-aminopyrimidine (1.0 g, 6.3 mmol) was diluted in EtOH (10 ml) and toluene (40 ml). A 2M Na₂CO₃ (7.9 ml) was added followed by Pd(PPh₃)₂Cl₂ (0.26 g, 0.38 mmol), and 2-chloro-4-trimfluoromethoxyphenyl boronic acid ((prepared as described in Arvanitis, A. G.; Rescinito, J. T.; Arnold, C. R.; Wilde, R. G.; Cain, G. A.; Sun, J. H.; Yan, J.-S., Teleha, C. A.; Fitzgerald, L. W.; McElroy, J.; Zaczek, R. Bioorg. Med. Chem. Lett., 2003, 13, 129) (1.5 g, 6.3 mmol). The reaction was warmed to reflux under an inert atmosphere for 5 hours. The reaction was then allowed to cool to room temperature and poured over EtOAc/H₂O. The organic layer was separated and washed with sat'd sodium chloride, dried (MgSO₄), filtered and concentrated. The material was flushed through a plug of silica using 100% EtOAc/hexane as an eluting solvent. The crude material was concentrated in vacuo. A portion of 6-(2-Methyl-4-trifluoromethoxy-phenyl)-pyrimidine-4,5-diamine (0.33 g, 1.0 mmol) was diluted in 10 mL butanol. (R)-1-Cyclopropyl-propylamine (0.33 g, 2.2 mmol) and triethylamine (0.57 mL, 4.0 mmol) was added to the solution and the mixture warmed to reflux for 18 hours. After concentrating the solution in vacuo and purification on silica gel using 100% EtOAc/hexane as the eluting solvent the desired intermediate (R)-N4-(1-cyclopropyl-propyl)-6-(2-methyl-4-trifluoromethoxy-phenyl)-pyrimidine-4,5-diamine was isolated (0.31 g, 79%). MS (AP) 387.3 [(M+H)+, 100].

[0788] Part B

[0789] (R)-N4-(1-Cyclopropyl-propyl)-6-(2-methyl-4-trifluoromethoxy-phenyl)-pyrimidine-4,5-diamine (0.31 g, 0.80 mmol) was diluted in ethanol (8 ml) and ethyl pyruvate was added (0.89 ml, 8.0 mmol). The mixture was stirred for 18 hours at which time the solution was concentrated. After concentrating the solution the product was purified by reverse phase HPLC to yield 6.0 mg of (R)-4-(2-Chloro-4-trifluoromethoxy-phenyl)-8-(1-cyclopropyl-propyl)-6-methyl-8H-pteridin-7-one (Example 1061a). ¹H NMR (300 MHz, CDCl₃) δ ppm 8.91 (s, 1 H), 7.47 (d, J=8.42 Hz, 1 H), 7.35 (d, J=1.10 Hz, 1 H), 7.22 (ddd, J=8.42, 2.29, 1.10 Hz, 1 H), 4.54 (m, 1 H), 2.45 (s, 3 H), 2.18 (m, 2 H), 1.32 (m, 1 H), 0.84 (m, 3 H), 0.68 (m, 1 H), 0.44 (m, 1 H), 0.30 (m, 1 H), 0.13 (m, 1 H).

Example 1062 4-(2-Chloro-4-trifluoromethoxy-phenyl)-8-(1-cyclopropyl-ethyl)-6-methyl-8H-pteridin-7-one

[0790] Part A

[0791] 6-(6-Methoxy-2-methyl-pyridin-3-yl)-pyrimidine-4,5-diamine (prepared substantially as described in Example 1061a) (0.23 g, 0.71 mmol) was diluted in 10 mL butanol. 1-Cyclopropyl-ethylamine (0.21 g, 1.6 mmol) and triethylamine (0.40 mL, 4.0 mmol) was added to the solution and the mixture warmed to reflux for 18 hours. After concentrating the solution in vacuo and purification on silica gel using 100% EtOAc/hexane as the eluting solvent the desired intermediate 6-(2-chloro-4-trifluoromethoxy-phenyl)-N4-(1-cyclopropyl-ethyl)-pyrimidine-4,5-diamine was isolated (0.20 g, 80%).

[0792] Part B

[0793] 6-(2-Chloro-4-trifluoromethoxy-phenyl)-N4-(1-cyclopropyl-ethyl)-pyrimidine-4,5-diamine (0.20 g, 0.52 mmol) was diluted in ethanol (6 ml) and ethyl pyruvate was added (0.58 ml, 5.2 mmol). The mixture was stirred for 18 hours at which time the solution was concentrated. After concentrating the solution the product was purified by reverse phase HPLC to yield 4.5 mg of 4-(2-chloro-4-trifluoromethoxy-phenyl)-8-(1-cyclopropyl-ethyl)-6-methyl-8H-pteridin-7-one (Example 1062). ¹H NMR (300 MHz, CDCl₃) δ ppm 8.99 (s, 1 H), 7.50 (d, J=8.79 Hz, 1 H), 7.39 (d, J=1.10 Hz, 1 H), 7.26 (dd, J=8.79, 1.10 Hz, 1 H), 4.91 (m, 1 H), 2.49 (s, 3 H), 1.71 (d, J=7.32, 3 H), 0.69 (m, 2 H), 0.41 (m, 2 H), 0.22 (m, 1 H). MS (EI) 425.2 [(M+H)+, 100].

Example 1067a (R)-4-(2-Chloro-4-trifluoromethoxy-phenyl)-8-(2-methoxy-1-methyl-ethyl)-6-methyl-8H-pteridin-7-one

[0794] Part A

[0795] 6-(6-Methoxy-2-methyl-pyridin-3-yl)-pyrimidine-4,5-diamineylamine (prepared substantially as described in Example 1061a) (0.25 g, 0.77 mmol) was diluted in 10 mL butanol. (R)-1-cyclopropyl-ethylamine (0.25 g, 1.7 mmol) and triethylamine (0.43 mL, 3.1 mmol) was added to the solution and the mixture warmed to reflux for 18 hours. After concentrating the solution in vacuo and purification on silica gel using 100% EtOAc/hexane as the eluting solvent the desired intermediate (R)-6-(2-chloro-4-trifluoromethoxy-phenyl)-N4-(2-methoxy-1-methyl-ethyl)-pyrimidine-4,5-diamine was isolated (0.20 g, 73%).

[0796] Part B

[0797] (R)-6-(2-Chloro-4-trifluoromethoxy-phenyl)-N4-(2-methoxy-1-methyl-ethyl)-pyrimidine-4,5-diamine (0.20 g, 0.53 mmol) was diluted in ethanol (6 ml) and ethyl pyruvate was added (0.59 ml, 5.3 mmol). The mixture was stirred for 18 hours at which time the solution was concentrated. After concentrating the solution the product was purified by reverse phase HPLC to yield 4.0 mg of (R)-4-(2-chloro-4-trifluoromethoxy-phenyl)-8-(2-methoxy-1-methyl-ethyl)-6-methyl-8H-pteridin-7-one (Example 1067a). ¹H NMR (300 MHz, CDCl₃) δ ppm 9.02 (s, 1 H), 7.49 (d, J=8.42 Hz, 1 H), 7.39 (d, J=1.10 Hz, 1 H), 7.26 (dd, J=8.42, 1.10 Hz, 1 H), 5.95 (s, 1 H), 4.36 (t, J=9.52 Hz, 1 H), 3.68 (dd, J=10.07, 5.31 Hz, 1 H), 3.30 (s, 3 H), 2.48 (s, 3 H), 1.58 (d, J=6.96 Hz, 3 H).

Example A Biological Assay

[0798] The compounds of the present invention can have CRF receptor antagonist activity. A compound can be considered active if it has a K_(i) value of less than about 10,000 nM for the inhibition of CRF. K_(i) values can be determined by any suitable biological assay, such as, for example, the assay described below.

[0799] Provided herein is an example of a CRF₁ receptor binding assay that can be used for the evaluation of biological activity of compounds of the present invention. The example also includes isolation of cell membranes containing cloned human CRF₁ receptors for use in the binding assay.

[0800] Messenger RNA is isolated from human hippocampus by standard techniques. The mRNA is reverse transcribed using oligo (dt) 12-18 and the coding region is amplified by PCR from start to stop codons The resulting PCR fragment is cloned into the EcoRV site of pGEMV, from whence the insert is reclaimed using XhoI+XbaI and cloned into the XhoI+XbaI sites of vector pm3ar (which contains a CMV promoter, the SV40 ‘t’ splice and early poly A signals, an Epstein-Barr viral origin of replication, and a hygromycin selectable marker). The resulting expression vector, called phchCRFR is transfected in 293EBNA cells, and cells retaining the episome are selected in the presence of 400 μM hygromycin. Cells surviving 4 weeks of selection in hygromycin are pooled, adapted to growth in suspension, and used to generate membranes for the binding assay described below. Individual aliquots containing approximately 1×10⁸ of the suspended cells are then centrifuged to form a pellet and frozen.

[0801] For the binding assay, a frozen pellet described above containing 293EBNA cells transfected with hCRFR1 receptors is homogenized in 10 mL of ice cold tissue buffer (50 mM HEPES buffer pH 7.0, containing 10 mM MgCl₂, 2 mM EGTA, 1 μg/l aprotinin, 1 μg/ml leupeptin and 1 μg/ml pepstatin). The homogenate is centrifuged at 40,000×g for 12 min and the resulting pellet rehomogenized in 10 mL of tissue buffer. After another centrifugation at 40,000×g for 12 min, the pellet is resuspended to a protein concentration of 360 μg/ml to be used in the assay.

[0802] Binding assays are performed in 96 well plates; each well having a 300 μL capacity. To each well is added 50 μL of test drug dilutions (final concentration of drugs range from 10⁻¹⁰ to 10⁻⁵ M), 100 μL of ¹²⁵I-ovine-CRF (¹²⁵I-o-CRF) (final concentration 150 pM) and 150 μL of the cell homogenate described above. Plates are then allowed to incubate at room temperature for 2 hours before filtering the incubate over GF/F filters (presoaked with 0.3% polyethyleneimine) using an appropriate cell harvester. Filters are rinsed 2 times with ice cold assay buffer before removing individual filters and assessing them for radioactivity on a gamma counter.

[0803] Curves of the inhibition of ¹²⁵I-o-CRF binding to cell membranes at various dilutions of test drug are analyzed by the iterative curve fitting program LIGAND Munson, et al., Anal. Biochem., 1980, 107, 220, which is incorporate herein by reference in its entirety, which provides K_(i) values for inhibition which are then used to assess biological activity.

[0804] Other in vitro assays for the determination of CRF₁ receptor antagonist activity of the present compounds are described, for example, in Endocrinology, 1985, 116, 1653 and in Peptides, 1985, 10, 179, each of which is incorporated by reference in its entirety. Receptor binding activity of compounds can also be evaluated according to the methods described in Grigoriadis, et al., Biochemical, Pharmacological, and Autoradiographic Methods to Study Corticotropin-Releasing Factor Receptors. Methods in Neurosciences, Vol. 5, 1991, which is incorporated herein by reference in its entirety.

Example B Inhibition of CRF-Stimulated Adenylate Cyclase Activity

[0805] Activity of the present compounds can be studied by the inhibition of CRF-stimulated adenylate cyclase activity which can be performed as described by Battaglia, et al., Synapse, 1987, 1, 572, which is incorporated herein by reference in its entirety. Assays are carried out at 37° C. for 10 min in 200 mL of buffer containing 100 mM Tris-HCl (pH 7.4 at 37° C.), 10 mM MgCl₂, 0.4 mM EGTA, 0.1% BSA, 1 mM isobutylmethylxanthine (IBMX), 250 units/ml phosphocreatine kinase, 5 mM creatine phosphate, 100 mM guanosine 5′-triphosphate, 100 nM oCRF, antagonist peptides (concentration range 10⁻⁹ to 10⁻⁶ M) and 0.8 mg original wet weight tissue (approximately 40-60 mg protein). Reactions are initiated by the addition of 1 mM ATP/³²P]ATP (approximately 2-4 mCi/tube) and terminated by the addition of 100 mL of 50 mM Tris-HCL, 45 mM ATP and 2% sodium dodecyl sulfate. In order to monitor the recovery of cAMP, 1 μL of [³H]cAMP (approximately 40,000 dpm) is added to each tube prior to separation. The separation of [³²P]cAMP from [³²P]ATP is performed by sequential elution over Dowex and alumina columns.

Example C In vivo Biological Assay

[0806] The in vivo activity of the compounds of the present invention can be assessed using any one of the biological assays available and accepted within the art. Examples of in vivo biological assays for testing axiolytic activity of compounds include the “punished drinking test” (Vogel, et al., Psychopharmcologia, 1971, 21, 1, which is incorporated herein by reference in its entirety); “elevated plus-maze test” (Pellow, et al., J. Neurosci. Methods, 1985, 14, 149, which is incorporated herein by reference in its entirety); “stress-induced coritcal norepinephrine release” (Funk, et al., Brain Res., 1996, 741, 220, which is incorporated herein by referenc ein its entirety); “light-dark test” (Misslin, et al., Behav. Process, 1989, 8, 119, which is incorporated herein by reference in its entirety); “four-plate test” (Boissier, et al., Eur. J. Pharmacol., 1968, 4, 145, which is incorporated herein by reference in its entirety); and “mouse defense test battery” (Griebel, et al., Aggress. Behav., 1997, 23, 19, which is incorporated herein by reference in its entirety). Compounds may be tested in any species of rodent or small mammal.

[0807] Examples of in vivo biological assays for testing antidepressant-like activity of compounds include the “forced swimming test” (Porsolt, et al., Nature, 1977, 266, 730, which is incorporated herein by reference in its entirety) and “CMS test” (Willner, et al., Clin. Neuropharmacol., 1992, 15 (supp. 1), 550A, which is incorporated herein by reference in its entirety).

[0808] Other models useful for the testing of compounds for their anxiolytic or antidepressant activity are outlined in Berridge, et al., Brain Research Reviews, 1990, 15, 71, which is incorporated herein by reference in its entirety. Models for testing activity of compounds for other indications are well known in the art.

[0809] As those skilled in the art will appreciate, numerous changes and modifications can be made to the preferred embodiments of the invention without departing from the spirit of the invention. It is intended that all such variations fall within the scope of the invention. Throughout this specification, various groupings are employed to conveniently describe constituent variables of compounds and groups of various related moieties. It is specifically intended that each occurrence of such groups throughout this specification include every possible subcombination of the members of the groups, including the individual members thereof.

[0810] It is intended that each of the patents, applications, and printed publications mentioned in this patent document be hereby incorporated by reference in its entirety. 

What is claimed is:
 1. A compound of Formula (I):

or a pharmaceutically acceptable salt form thereof, or prodrug thereof, or radiolabeled form thereof, wherein: A and B are independently CR⁴ or N, with the proviso that at least one of A and B is N; Ar is aryl or heteroaryl, wherein said aryl or heteroaryl is optionally substituted by one or more substituents independently selected from C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, halogen, CN, NO₂, OR⁵, and SR⁵; R¹ is H, CN, C₁-C₄ haloalkyl, NR^(1c)R^(1d), NR^(1c)COR^(1b), COR^(1b), CONR^(1c)R^(1d), OR^(1c), SR^(1c), C₁-C₄ alkyl substituted with 0 to 3 R^(1a), C₂-C₄ alkenyl substituted with 0 to 3 R^(1a), C₂-C₄ alkynyl substituted with 0 to 3 R^(1a), C₃-C₆ cycloalkyl substituted with 0 to 3 R^(1a), or C₄-C₈ cycloalkylalkyl substituted with 0 to 3 R^(1a), with the proviso that R¹ is not CH₂X, wherein X is halogen; each R^(1a) is, independently at each occurrence, halogen, CN, N₃, NO₂, C₁-C₂ haloalkyl, NR^(1c)R^(1d), NR^(1c)COR^(1b), COR^(1b), OR^(1c), SR^(1c), S(O)R⁸, or S(O)₂R⁸; each R^(1b) is, independently at each occurrence, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₃-C₆ cycloalkyl, C₂-C₄ alkenyl, or C₂-C₄ alkynyl; each R^(1c) is, independently at each occurrence, selected from H, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₃-C₆ cycloalkyl, C₂-C₄ alkenyl, or C₂-C₄ alkynyl; each R^(1d) is, independently at each occurrence, selected from H, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₃-C₆ cycloalkyl, C₂-C₄ alkenyl, or C₂-C₄ alkynyl; R² is H, C₁-C₃ haloalkyl, CN, OH, COR^(2b), SH, SR^(2b), SO₂NHR^(2c), SO₂NR^(2c)R^(2d), CONHR^(2c), CONR^(2c)R^(2d), OCOR^(2b), OR^(2b), NR^(2c)R^(2d), CO₂R^(2b), C₁-C₄ alkyl substituted with 0 to 3 R^(2a), C₂-C₄ alkenyl substituted with 0 to 3 R^(2a), C₂-C₄ alkynyl substituted with 0 to 3 R^(2a), or C₃-C₆ cycloalkyl substituted with 0 to 3 R^(2a); with the proviso that R² is not CH₂X, wherein X is halogen; each R^(2a) is, independently at each occurrence, halogen, CN, N₃, NO₂, CF₃, OR^(2c), NR^(2c), NR^(2c)R^(2d), NR^(2c)CO₂R^(2b), SR^(2c), SOR⁸, SO₂R⁸, CO₂R^(2b), CONR^(2c)R^(2d), COR^(2b), OCOR^(2b), NR^(2c)CONR^(2c)R^(2d), NR^(2c)CO₂R^(2b), OCONR^(2c)R^(2d), piperidinyl, pyrrolidinyl, piperazinyl, N-methylpiperazinyl, morpholinyl, or thiomorpholinyl; each R^(2b) is, independently at each occurrence, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₃-C₆ cycloalkyl, C₄-C₁₂ cycloalkylalkyl, aryl, heteroaryl, aryl-C₁-C₄ alkyl, or heteroaryl-C₁-C₄ alkyl; each R^(2c) is, independently at each occurrence, H, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₃-C₆ cycloalkyl, C₄-C₁₂ cycloalkylalkyl aryl, heteroaryl, aryl-C₁-C₄ alkyl, or heteroaryl-C₁-C₄ alkyl; each R^(2d) is, independently at each occurrence, H, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₃-C₆ cycloalkyl, C₄-C₁₂ cycloalkylalkyl aryl, heteroaryl, aryl-C₁-C₄ alkyl, or heteroaryl-C₁-C₄ alkyl; R³ is OR^(3c), NR^(3c)R^(3d), NHR^(3c), SR^(3c), SOR⁸, SO₂R⁸, SO₂NHR^(3c), SO₂NR^(3c)R^(3d), COR^(3c), CONHR^(3c), CONR^(3c)R^(3d), aryl substituted with 0 to 3 R^(3a), heteroaryl substituted with 0 to 3 R^(3a), heterocyclyl substituted with 0 to 3 R^(3f), C₁-C₁₀ alkyl substituted with 0 to 3 R^(3a), C₃-C₁₀ alkenyl substituted with 0 to 3 R^(3a), C₃-C₁₀ alkynyl substituted with 0 to 3 R^(3a), C₃-C₈ cycloalkyl substituted with 0 to 3 R^(3a), C₄-C₁₂ cycloalkylalkyl substituted with 0 to 3 R^(3a), C₂-C₁₀ alkoxyalkyl substituted with 0 to 3 R^(3a), C₂-C₁₀ thioalkoxyalkyl substituted with 0 to 3 R^(3a), C₅-C₁₀ cycloalkenyl substituted with 0 to 3 R^(3a), or C₆-C₁₀ cycloalkenylalkyl substituted with 0 to 3 R^(3a), wherein one carbon in any cycloalkyl moiety is optionally replaced with O, S or NR⁵; each R^(3a) is, independently at each occurrence, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₆ cycloalkyl, halogen, C₁-C₄ haloalkyl, CN, OR^(3c), SR^(3c), S(O)R⁸, S(O)₂R⁸, COR^(3b), NHR^(3c)SO₂R^(3b), OC(O)NR^(3c)R^(3d), N₃, OC(O)OR^(3b), CO₂R^(3c), OC(O)R^(3b), NR^(3c)COR^(3b), N(COR^(3b))₂, NR^(3c)CONR^(3c)R^(3d), NR^(3c)CO₂R^(3b), NR^(3c)R^(3d), CONR^(3c)R^(3d), aryl, heteroaryl, or heterocyclyl; each R^(3b) is, independently at each occurrence, C₁-C₁₀ alkyl substituted with 0 to 3 R^(3e), C₂-C₁₀ alkenyl substituted with 0 to 3 R^(3e), C₂-C₁₀ alkynyl substituted with 0 to 3 R^(3e), C₃-C₈ cycloalkyl substituted with 0 to 3 R^(3e), C₄-C₁₂ cycloalkylalkyl substituted with 0 to 3 R^(3e), C₂-C₁₀ alkoxyalkyl substituted with 0 to 3 R^(3e), C₅-C₁₀ cycloalkenyl substituted with 0 to 3 R^(3e), or C₆-C₁₀ cycloalkenylalkyl substituted with 0 to 3 R^(3e), wherein one carbon in any cycloalkyl moiety is optionally replaced with O, S or NR⁵; each R^(3c) is, independently at each occurrence, H, C₁-C₁₀ alkyl substituted with 0 to 3 R^(3e), C₂-C₁₀ alkenyl substituted with 0 to 3 R^(3e), C₂-C₁₀ alkynyl substituted with 0 to 3 R^(3e), C₃-C₈ cycloalkyl substituted with 0 to 3 R^(3e), C₄-C₁₂ cycloalkylalkyl substituted with 0 to 3 R^(3e), C₂-C₁₀ alkoxyalkyl substituted with 0 to 3 R^(3e), C₅-C₁₀ cycloalkenyl substituted with 0 to 3 R^(3e), or C₆-C₁₀ cycloalkenylalkyl substituted with 0 to 3 R^(3e), wherein one carbon in any cycloalkyl moiety is optionally replaced with O, S or NR⁵; each R^(3d) is, independently at each occurrence, H, C₁-C₁₀ alkyl substituted with 0 to 3 R^(3e), C₂-C₁₀ alkenyl substituted with 0 to 3 R^(3e), C₂-C₁₀ alkynyl substituted with 0 to 3 R^(3e), C₃-C₈ cycloalkyl substituted with 0 to 3 R^(3e), C₄-C₁₂ cycloalkylalkyl substituted with 0 to 3 R^(3e), C₂-C₁₀ alkoxyalkyl substituted with 0 to 3 R^(3e), C₅-C₁₀ cycloalkenyl substituted with 0 to 3 R^(3e), or C₆-C₁₀ cycloalkenylalkyl substituted with 0 to 3 R^(3e), wherein one carbon in any cycloalkyl moiety is optionally replaced with O, S or NR⁵; each R^(3e) is, independently at each occurrence, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₁₀ alkynyl, C₃-C₆ cycloalkyl, halogen, C₁-C₄ haloalkyl, CN, OR^(7a), SR^(7a), S(O)_(n)R⁸, COR⁶, CO₂R^(7a), OC(O)R⁶, NR^(7a)COR⁶, N(COR⁶)₂, NR^(7a)CONR^(7a)R^(7b), NR^(7a)CO₂R⁶, NR^(7a)R^(7b), NHR^(7a)SO₂R⁶, OC(O)NR^(7a)R^(7b), N₃, OC(O)OR⁶, CONR^(7a)R^(7b), aryl, heteroaryl, or heterocyclyl; each R^(3f) is, independently at each occurrence, oxo, sulfido, or R^(3a); R⁴ is H, halogen, CN, C₁-C₃ haloalkyl, COR^(4b), OR^(4c), SR^(4c), SO₂NHR^(4c), SO₂NR^(4c)R^(4d), CONHR^(4c), CONR^(4c)R^(4d), OCOR^(4b), NR^(4c)CONHR^(4c), NR^(4c)CONR^(4c)R^(4d), NR^(4c)CO₂R^(4b), OCONR^(4c)R^(4d), NR^(4c)R^(4d), CO₂R^(4b), C₁-C₄ alkyl substituted with 0 to 1 R^(4a), C₂-C₄ alkenyl substituted with 0 to 1 R^(4a), C₂-C₄ alkynyl substituted with 0 to 1 R^(4a), C₃-C₆ cycloalkyl substituted with 0 to 1 R^(4a), piperidinyl, pyrrolidinyl, piperazinyl, N-methylpiperazinyl, morpholinyl, or thiomorpholinyl; each R^(4a) is, independently at each occurrence, halogen, CN, CF₃, OR^(4c), NHR^(4c), NR^(4c)R^(4d), NR^(4c)CO₂R^(4b), SR^(4c), SOR⁸, SO₂R⁸, CO₂R^(4b), CONHR^(4c), CONR^(4c)R^(4d), COR^(4b), OCOR^(4b), NR^(4c)CONR^(4c)R^(4d), NR^(4c)CO₂R^(4b), OCONR^(4c)R^(4d), piperidinyl, pyrrolidinyl, piperazinyl, N-methylpiperazinyl, morpholinyl, or thiomorpholinyl; each R^(4b) is, independently at each occurrence, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₃-C₆ cycloalkyl, C₄-C₁₂ cycloalkylalkyl, aryl, heteroaryl, aryl-C₁-C₄ alkyl, or heteroaryl-C₁-C₄ alkyl; each R^(4c) is, independently at each occurrence, H, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₃-C₆ cycloalkyl, C₄-C₁₂ cycloalkylalkyl, aryl, heteroaryl, aryl-C₁-C₄ alkyl, or heteroaryl-C₁-C₄ alkyl; each R^(4d) is, independently at each occurrence, H, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₃-C₆ cycloalkyl, C₄-C₁₂ cycloalkylalkyl, aryl, heteroaryl, aryl-C₁-C₄ alkyl, or heteroaryl-C₁-C₄ alkyl; R⁵ is H, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, or C₂-C₆ alkoxyalkyl; R⁶ is, independently at each occurrence, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₁₂ cycloalkylalkyl, C₂-C₈ alkoxyalkyl, C₅-Cl₂ bis(alkoxy)alkyl, aryl, aryl-C₁-C₄ alkyl, heteroaryl, or heteroaryl-C₁-C₄ alkyl; each R^(7a) is, independently at each occurrence, H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₁₂ cycloalkylalkyl, C₂-C₈ alkoxyalkyl, C₅-C₁₂ bis(alkoxy)alkyl, aryl, aryl-C₁-C₄ alkyl, heteroaryl, or heteroaryl-C₁-C₄ alkyl; each R^(7b) is, independently at each occurrence, H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₁₂ cycloalkylalkyl, C₂-C₈ alkoxyalkyl, C₅-C₁₂ bis(alkoxy)alkyl, aryl, aryl-C₁-C₄ alkyl, heteroaryl, or heteroaryl-C₁-C₄ alkyl; and R⁸ is C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₃-C₆ cycloalkyl, C₄-C₁₂ cycloalkylalkyl, aryl, heteroaryl, aryl-C₁-C₄ alkyl, or heteroaryl-C₁-C₄ alkyl, or NR^(7a)R^(7b).
 2. The compound of claim 1, of Formula (Ia):


3. The compound of claim 2 wherein A is N.
 4. The compound of claim 2 wherein A is CR⁴.
 5. The compound of claim 2 wherein Ar is aryl.
 6. The compound of claim 5 wherein said aryl is phenyl substituted with 0 to 5 substituents or naphthyl substituted with 0 to 7 substituents, wherein each of said substituents is independently selected from, at each occurrence, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, halogen, CN, NO₂, OR⁵, and SR⁵.
 7. The compound of claim 2 wherein Ar is heteroaryl.
 8. The compound of claim 7 wherein said heteroaryl comprises a six-membered ring.
 9. The compound of claim 8 wherein said heteroaryl is pyridyl or pyrimidinyl, wherein said heteroaryl is substituted with 0 to 4 substituents, wherein each of said substituents is independently selected from, at each occurrence, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, halogen, CN, NO₂, OR⁵, and SR⁵.
 10. The compound of claim 7 wherein said heteroaryl comprises a five-membered ring.
 11. The compound of claim 10 wherein said heteroaryl is oxazolyl, isoxazolyl, or thienyl, wherein said heteroaryl is substituted with 0 to 4 substituents, wherein each of said substituents is independently selected from, at each occurrence, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, halogen, CN, NO₂, OR⁵, and SR⁵.
 12. The compound of claim 2 wherein R¹ is H, CN, OH, C₁-C₄ alkyl, or C₁-C₂ haloalkyl.
 13. The compound of claim 2 wherein R¹ is C₁-C₄ alkyl.
 14. The compound of claim 2 wherein R² is H, CN, OH, SH, OR^(2b), SR^(2b), C₁-C₃ haloalkyl, or C₁-C₄ alkyl substituted with 0 to 3 R^(2a).
 15. The compound of claim 2 wherein R² is H.
 16. The compound of claim 2 wherein R³ is S(O)R⁸, S(O)₂R⁸, COR^(3c), CONHR^(3c), CONR^(3c)R^(3d), C₁-C₈ alkyl substituted with 0 to 3 R^(3a), C₃-C₈ alkenyl substituted with 0 to 3 R^(3a), C₃-C₈ alkynyl substituted with 0 to 3 R^(3a), C₃-C₆ cycloalkyl substituted with 0 to 3 R^(3a), or C₄-C₁₀ cycloalkylalkyl substituted with 0 to 3 R^(3a), wherein one carbon in any cycloalkyl moiety is optionally replaced with O, S or NR⁵.
 17. The compound of claim 2 wherein R³ is C₁-C₆ alkyl substituted with 0 to 2 R^(3a).
 18. The compound of claim 2 wherein each R^(3a) is, independently at each occurrence, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, F, Cl, Br, CF₃, CN, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, OR^(3c), SR^(3c), COR^(3b), NHR^(3c)SO₂R^(3b), OC(O)NR^(3c)R^(3d), N₃, OC(O)OR^(3b), CO₂R^(3c), OC(O)R^(3b), NR^(3c)COR^(3b), N(COR^(3b))₂, NR^(3c)CONR^(3c)R^(3d), NR^(3c)CO₂R^(3b), NR^(3c)R^(3d), or CONR^(3c)R^(3d).
 19. The compound of claim 2 wherein R⁴ is H, CN, OH, C₁-C₄ alkyl, C₁-C₃ haloalkyl, SR^(4c), or OR^(4c).
 20. The compound of claim 2 wherein R⁴ is H.
 21. A compound of claim 2 wherein: R¹ is H, CN, OH, SH, C₁-C₄ haloalkyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, C₁-C₄ alkyl substituted with 0 to 3 R^(1a), C₂-C₄ alkenyl substituted with 0 to 3 R^(1a), or C₂-C₄ alkynyl substituted with 0 to 3 R^(1a); R^(1a) is F, Cl, Br, CN, NO₂, OH, OCH₃, CF₃, CHF₂, or OCF₃; R² is H, CN, OH, NR^(2c)R^(2d), C₁-C₃ alkyl substituted with 0 to 3 R^(2a), C₁-C₃ alkoxy, C₁-C₂ haloalkyl, or C₁-C₂ haloalkoxy; R³ is SOR⁸, SO₂R⁸, SO₂NR^(3c)R^(3d), COR^(3c), CONHR^(3c), CONR^(3c)R^(3d), aryl substituted with 0 to 3 R^(3a), heteroaryl substituted with 0 to 3 R^(3a), heterocyclyl substituted with 0 to 3 R^(3f), C₁-C₁₀ alkyl substituted with 0 to 3 R^(3a), C₃-C₁₀ alkenyl substituted with 0 to 3 R^(3a), C₃-C₁₀ alkynyl substituted with 0 to 3 R^(3a), C₃-C₈ cycloalkyl substituted with 0 to 3 R^(3a), C₄-C₁₂ cycloalkylalkyl substituted with 0 to 3 R^(3a), C₂-C₁₀ alkoxyalkyl substituted with 0 to 3 R^(3a), C₂-C₁₀ thioalkoxyalkyl substituted with 0 to 3 R^(3a), C₅-C₁₀ cycloalkenyl substituted with 0 to 3 R^(3a), or C₆-C₁₀ cycloalkenylalkyl substituted with 0 to 3 R^(3a), wherein one carbon in any cycloalkyl moiety is optionally replaced with O, S or NR⁵; R⁴ is H, halogen, CN, C₁-C₃ haloalkyl, OR^(4c), SR^(4c), NR^(4c)R^(4d), CO₂R^(4b), C₁-C₄ alkyl substituted with 0 to 1 R^(4a), or C₃-C₆ cycloalkyl substituted with 0 to 1 R^(4a); each R^(4a) is, independently at each occurrence, halogen, CN, CF₃, OR^(4c), NHR^(4c), NR^(4c)R^(4d), NR^(4c)CO₂R^(4b), SR^(4c), SOR⁸, SO₂R⁸, CO₂R^(4b), CONHR^(4c), CONR^(4c)R^(4d), COR^(4b), OCOR^(4b), NR^(4c)CONR^(4c)R^(4d), NR^(4c)CO₂R^(4b), OCONR^(4c)R^(4d); R⁵ is H, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, or C₂-C₆ alkoxyalkyl; each R^(7a) is, independently at each occurrence, H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₄-C₁₂ cycloalkylalkyl, or C₂-C₈ alkoxyalkyl; and each R^(7b) is, independently at each occurrence, H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₄-C₁₂ cycloalkylalkyl, or C₂-C₈ alkoxyalkyl.
 22. The compound of claim 21 wherein A is N.
 23. The compound of claim 21 wherein A is CR⁴.
 24. The compound of claim 21 wherein R¹ is H, CN, OH, C₁-C₄ alkyl, or C₁-C₂ haloalkyl.
 25. The compound of claim 21 wherein R² is H, CN, OH, methyl, ethyl, methoxy, OCF₃, CF₃, CHF₂, CH₂CF₃, or CF₂CH₃.
 26. The compound of claim 21 wherein R² is H.
 27. The compound of claim 21 wherein R³ is C₁-C₆ alkyl substituted with 0 to 2 R^(3a).
 28. The compound of claim 21 wherein R⁴ is H, CN, OH, C₁-C₄ alkyl, C₁-C₃ haloalkyl, SR^(4c), or OR^(4c).
 29. The compound of claim 21 wherein R⁴ is H.
 30. The compound of claim 21 wherein Ar is aryl.
 31. The compound of 30 wherein said aryl is phenyl substituted with 0 to 5 substituents or naphthyl substituted with 0 to 7 substituents, wherein each of said substituents is independently selected from, at each occurrence, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, halogen, CN, NO₂, OR⁵, and SR⁵.
 32. The compound of claim 21 wherein Ar is heteroaryl.
 33. The compound of claim 32 wherein said heteroaryl comprises a six-membered ring.
 34. The compound of claim 33 wherein said heteroaryl is pyridyl or pyrimidinyl, wherein said heteroaryl is substituted with 0 to 4 substituents, wherein each of said substituents is independently selected from, at each occurrence, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, halogen, CN, NO₂, OR⁵, and SR⁵.
 35. The compound of claim 32 wherein said heteroaryl comprises a five-membered ring.
 36. The compound of claim 35 wherein said heteroaryl is oxazolyl, isoxazolyl, or thienyl, wherein said heteroaryl is substituted with 0 to 4 substituents, wherein each of said substituents is independently selected from, at each occurrence, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, halogen, CN, NO₂, OR⁵, and SR⁵.
 37. A compound of claim 21 wherein: Ar is phenyl, pyridyl, pyrimidinyl, oxazolyl, isoxazolyl, or thienyl, wherein said phenyl is substituted with 0 to 5 R^(9a) and said pyridyl, pyrimidinyl, oxazolyl, isoxazolyl, or thienyl is substituted with 0 to 4 R^(9b); R¹ is H, CN, methyl, ethyl, methoxy, OH, or C₁-C₂ haloalkyl; R² is H, CN, OH, CH₃, OCH₃, CF₃, CHF₂, or OCF₃; R³ is S(O)R⁸, S(O)₂R⁸, COR^(3c), CONHR^(3c), CONR^(3c)R^(3d), C₁-C₈ alkyl substituted with 0 to 3 R^(3a), C₃-C₈ alkenyl substituted with 0 to 3 R^(3a), C₃-C₈ alkynyl substituted to 3 R^(3a), C₃-C₆ cycloalkyl substituted with 0 to 3 R^(3a), or C₄-C₁₀ cycloalkylalkyl substituted with 0 to 3 R^(3a), wherein one carbon in any cycloalkyl moiety is optionally replaced with O, S or NR⁵; each R^(3a) is, independently at each occurrence, methyl, ethyl, methoxy, ethoxy, thiomethoxy, thioethoxy, cyclopropyl, cyclobutyl, F, Cl, CF₃ CHF₂, CH₃, or OCF₃; R⁴ is H, CHF₂, CF₃, methyl, ethyl, Cl, F, OH, SH, methoxy, thiomethoxy, CH₂CF₃, CF₂CH₃; and each R^(9a) and R^(9b) is, independently at each occurrence, F, Cl, Br, CN, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, isopropoxy, C₁-C₂ haloalkyl, or C₁-C₂ haloalkoxy.
 38. The compound of claim 37 wherein A is N.
 39. The compound of claim 37 wherein A is CR⁴.
 40. The compound of claim 37 wherein R² is H.
 41. The compound of claim 37 wherein R³ is butyl, pentyl, hexyl, heptyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, methoxyhexyl, thiomethoxyethyl, thiomethoxypropyl, thiomethoxybutyl, thiomethoxypentyl, thiomethoxyhexyl, 1-cyclopropylpropyl, 1-cyclopropylbutyl, 1-cyclopropylpentyl, 1-cyclobutylpropyl, 1-cyclobutylbutyl, 1-cyclobutylpentyl, 1-cyclopropyl-1-(CF₃)-methyl, 1-cyclopropyl-1-(CF₃)-ethyl, 1-cyclopropyl-1-(CF₃)-propyl, 1-cyclobutyl-1-(CF₃)-methyl, 1-cyclobutyl-2-(CF₃)-ethyl, 1-cyclobutyl-3-(CF₃)-propyl, or (cyclopropyl)₂CH.
 42. The compound of claim 37 wherein R⁴ is H.
 43. The compound of claim 37 wherein Ar is phenyl substituted with 0 to 5 R^(9a).
 44. The compound of claim 37 wherein Ar is pyridyl substituted with 0 to 4 R^(9b) or pyrimidinyl substituted with 0 to 4 R^(9b).
 45. A compound of claim 37 wherein: Ar is phenyl substituted with 0 to 3 substituents each independently selected from F, Cl, Br, CN, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, isopropoxy, CF₃, CHF₂, and OCF₃; or Ar is pyridyl or pyrimidinyl substituted with 0 to 2 substituents each independently selected from F, Cl, Br, CN, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, isopropoxy, CF₃, CHF₂, and OCF₃; R¹ is H, CN, OH, methyl, ethyl, methoxy, or C₁-C₂ haloalkyl; R² is H; R³ is C₁-C₆ alkyl substituted with 0 to 2 R^(3a); and R⁴ is H.
 46. The compound of claim 45 wherein Ar is phenyl substituted with 0 to 3 substituents each independently selected from F, Cl, Br, CN, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, isopropoxy, CF₃, CHF₂, and OCF₃.
 47. The compound of claim 45 wherein Ar is pyridyl or pyrimidinyl substituted with 0 to 2 substituents each independently selected from F, Cl, Br, CN, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, isopropoxy, CF₃, CHF₂, and OCF₃.
 48. The compound of claim 47 wherein said pyridyl is pyrid-3-yl.
 49. The compound of claim 45 wherein A is N.
 50. The compound of claim 45 wherein A is CR⁴.
 51. The compound of claim 45 wherein R³ is butyl, pentyl, hexyl, heptyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, methoxyhexyl, thiomethoxyethyl, thiomethoxypropyl, thiomethoxybutyl, thiomethoxypentyl, thiomethoxyhexyl, 1-cyclopropylpropyl, 1-cyclopropylbutyl, 1-cyclopropylpentyl, 1-cyclobutylpropyl, 1-cyclobutylbutyl, 1-cyclobutylpentyl, 1-cyclopropyl-1-(CF₃)-methyl, 1-cyclopropyl-1-(CF₃)-ethyl, 1-cyclopropyl-1-(CF₃)-propyl, 1-cyclobutyl-1-(CF₃)-methyl, 1-cyclobutyl-2-(CF₃)-ethyl, 1-cyclobutyl-3-(CF₃)-propyl, or (cyclopropyl)₂CH.
 52. A compound of claim 2 selected from: (R)-8-(2,4-dichloro-phenyl)-4-isobutyl-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one; (S)-8-(2,4-dichloro-phenyl)-4-isobutyl-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one; (R)-8-(2,4-dichloro-phenyl)-2-methyl-4-(1-methyl-butyl)-4H-pyrido[2,3-b]pyrazin-3-one; (S)-8-(2,4-dichloro-phenyl)-2-methyl-4-(1-methyl-butyl)-4H-pyrido[2,3-b]pyrazin-3-one; (S)-4-(1-cyclopropyl-propyl)-8-(2,4-dichloro-phenyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one; (R)-4-(1-cyclopropyl-propyl)-8-(2,4-dichloro-phenyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one; (R)-8-(2,4-dichloro-phenyl)-4-(1,2-dimethyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one; (S)-8-(2,4-dichloro-phenyl)-4-(1,2-dimethyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one; (R)-4-(1-cyclopropyl-butyl)-8-(2,4-dichloro-phenyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one; (S)-4-(1-cyclopropyl-butyl)-8-(2,4-dichloro-phenyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one; (R)-8-(2,4-dichloro-phenyl)-4-(2-methoxy-1-methyl-ethyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one; (S)-8-(2,4-dichloro-phenyl)-4-(2-methoxy-1-methyl-ethyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one; (S)-8-(2,4-dichloro-phenyl)-4-(1-methoxymethyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one; (R)-8-(2,4-dichloro-phenyl)-4-(1-methoxymethyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one; (R,S)-8-(2-chloro-4-methoxy-phenyl)-2-methyl-4-(1-propyl-butyl)-4H-pyrido[2,3-b]pyrazin-3-one; (S)-8-(2-chloro-4-methoxy-phenyl)-4-(1-cyclopropyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one; (R)-8-(2-chloro-4-methoxy-phenyl)-4-(1-cyclopropyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one; (R)-8-(2-chloro-4-methoxy-phenyl)-4-(1-cyclobutyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one; (S)-8-(2-chloro-4-methoxy-phenyl)-4-(1-cyclobutyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one; (S)-8-(2-chloro-4-methoxy-phenyl)-4-(2-methoxy-1-methyl-ethyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one; (R)-8-(2-chloro-4-methoxy-phenyl)-4-(2-methoxy-1-methyl-ethyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one; (S)-8-(2-chloro-4-methoxy-phenyl)-4-(1-methoxymethyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one; (R)-4-(1-cylcopropropyl-propyl)-8-(4-methoxy-2-methyl-phenyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one; (R)-4-(1-cyclopropyl-butyl)-8-(4-methoxy-2-methyl-phenyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one; (S)-4-(1-cyclopropyl-butyl)-8-(4-methoxy-2-methyl-phenyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one; (R)-4-(2-methoxy-1-methyl-ethyl)-8-(4-methoxy-2-methyl-phenyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one; (R)-4-(1-ethyl-pentyl)-8-(6-methoxy-2-methyl-pyridin-3-yl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one; (S)-4-(1-ethyl-pentyl)-8-(6-methoxy-2-methyl-pyridin-3-yl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one; (R)-4-(1-cyclopropyl-propyl)-8-(6-methoxy-2-methyl-pyridin-3-yl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one; (R)-4-(1-cyclopropyl-butyl)-8-(6-methoxy-2-methyl-pyridin-3-yl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one; (S)-4-(1-cyclopropyl-butyl)-8-(6-methoxy-2-methyl-pyridin-3-yl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one; (R)-4-(2-methoxy-1-methyl-ethyl)-8-(6-methoxy-2-methyl-pyridyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one; (R)-4-sec-butyl-8-(2-chloro-4-difluoromethoxy-phenyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one; (S)-4-(1-cyclopropyl-butyl)-8-(6-methoxy-2-methyl-pyridin-3-yl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one; (S)-8-(2-chloro-4-difluoromethoxy-phenyl)-4-(1-cyclopropyl-propyl)2-methyl-4H-pyrido[2,3-b]pyrazin-3-one; (R)-8-(2-chloro-4-difluoromethoxy-phenyl)-4-(1-cyclopropyl-propyl)2-methyl-4H-pyrido[2,3-b]pyrazin-3-one; (R)-8-(2-chloro-4-difluoromethoxy-phenyl)-4-(1-cyclopropyl-butyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one; (S)-8-(2-chloro-4-difluoromethoxy-phenyl)-4-(1-cyclopropyl-butyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one; (R)-8-(2-chloro-4-difluoromethoxy-phenyl)-4-(2-methoxy-1-methyl-ethyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one; (R)-8-(2-chloro-4-difluoromethoxy-phenyl)-4-(1-methoxymethyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one; (S)-8-(2-chloro-4-difluoromethoxy-phenyl)-4-(1-methoxymethyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one; (S)-8-(2-chloro-4-trifluoromethyl-phenyl)-4-(1-cyclopropyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one; (R)-8-(2-chloro-4-trifluoromethyl-phenyl)-4-(2-methoxy-1-methyl-ethyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one; (R)-8-(2-chloro-4-trifluoromethyl-phenyl)-4-(1-methoxymethyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one; (R)-3-chloro-4-(4-(1-methoxymethylpropyl)-2-methyl-3-oxo-3,4-dihydro-pyrido[2,3-b]pyrazin-8-yl]-benzonitrile; (R)-8-sec-butyl-4-(2,4-dichloro-phenyl)-6-methyl-8H-pteridin-7-one; and (S)-8-sec-butyl-4-(2,4-dichloro-phenyl)-6-methyl-8H-pteridin-7-one.
 53. A compound of claim 2 selected from: (R,S)-8-(4-Methoxy-2-methyl-phenyl)-4-(1-methoxymethyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one; (R)-4-(1-Cyclopropyl-propyl)-8-(5-fluoro-4-methoxy-2-methyl-phenyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one; (R)-8-(5-Fluoro-4-methoxy-2-methyl-phenyl)-4-(1-methoxymethyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one; (S)-8-(2-Chloro-5-fluoro-4-methoxy-phenyl)-4-(1-cyclopropyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one; 8-(2-Chloro-5-fluoro-4-methoxy-phenyl)-4-(1-methoxymethyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one; 8-(5-Chloro-4-methoxy-2-methyl-phenyl)-4-(1-cyclopropyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one; 8-(5-Chloro-4-methoxy-2-methyl-phenyl)-4-(1-methoxymethyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one; 8-(2-Chloro-4-methoxy-5-methyl-phenyl)-4-(1-cyclopropyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one; 8-(2-Chloro-4-methoxy-5-methyl-phenyl)-4-(1-methoxymethyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one; 8-(2-Chloro-4-dimethylamino-5-fluoro-phenyl)-4-(1-cyclopropyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one; (R)-8-(2-Chloro-4-dimethylamino-5-fluoro-phenyl)-4-(1-cyclopropyl-ethyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one; (R)-8-(2-Chloro-4-dimethylamino-5-fluoro-phenyl)-4-(1-cyclobutyl-ethyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one; 8-(2-Chloro-4-dimethylamino-5-fluoro-phenyl)-4-(2-methoxy-1-methyl-ethyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one; 8-(2-Chloro-4-dimethylamino-5-fluoro-phenyl)-4-(1-methoxymethyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one; 4-(2-Chloro-4-methoxy-phenyl)-6-methyl-8-(1-propyl-butyl)-8H-pteridin-7-one; (R)-4-(2-Chloro-4-methoxy-phenyl)-8-(1-cyclopropyl-ethyl)-6-methyl-8H-pteridin-7-one; (S)-4-(2-Chloro-4-methoxy-phenyl)-8-(1-cyclobutyl-ethyl)-6-methyl-8H-pteridin-7-one; (R)-4-(2-Chloro-4-methoxy-phenyl)-8-(2-methoxy-1-methyl-ethyl)-6-methyl-8H-pteridin-7-one; (R)-4-(2-Chloro-4-methoxy-phenyl)-8-(1-methoxymethyl-propyl)-6-methyl-8H-pteridin-7-one; (R)-8-(1-Cyclopropyl-propyl)-4-(4-methoxy-2-methyl-phenyl)-6-methyl-8H-pteridin-7-one; (R)-8-(1-Cyclopropyl-propyl)-4-(6-methoxy-2-methyl-pyridin-3-yl)-6-methyl-8H-pteridin-7-one; (R)-8-(2-Methoxy-1-methyl-ethyl)-4-(6-methoxy-2-methyl-pyridin-3-yl)-6-methyl-8H-pteridin-7-one; (R)-8-(1-Methoxymethyl-propyl)-4-(6-methoxy-2-methyl-pyridin-3-yl)-6-methyl-8H-pteridin-7-one; (R)-4-(4-Methoxy-2,5-dimethyl-phenyl)-8-(1-methoxymethyl-propyl)-6-methyl-8H-pteridin-7-one; (R)-4-(2-Chloro-4-trifluoromethoxy-phenyl)-8-(1-cyclopropyl-propyl)-6-methyl-8H-pteridin-7-one; 4-(2-Chloro-4-trifluoromethoxy-phenyl)-8-(1-cyclopropyl-ethyl)-6-methyl-8H-pteridin-7-one; and (R)-4-(2-Chloro-4-trifluoromethoxy-phenyl)-8-(2-methoxy-1-methyl-ethyl)-6-methyl-8H-pteridin-7-one.
 54. A compound of claim 1 selected from the group consisting of: (R)-5-(2,4-Dichloro-phenyl)-1-isobutyl-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (S)-5-(2,4-Dichloro-phenyl)-1-isobutyl-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (R)-1-(1-Cyclopropyl-propyl)-5-(2,4-dichloro-phenyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (S)-1-(1-Cyclopropyl-propyl)-5-(2,4-dichloro-phenyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (R)-5-(2,4-Dichloro-phenyl)-1-(1-methoxymethyl-propyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (S)-5-(2,4-Dichloro-phenyl)-1-(1-methoxymethyl-propyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (R)-5-(2,4-Dichloro-phenyl)-1-(2-methoxy-1-methyl-ethyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (S)-5-(2,4-Dichloro-phenyl)-1-(2-methoxy-1-methyl-ethyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (R)-1-(1-Cyclopropyl-2-methoxy-ethyl)-5-(2,4-dichloro-phenyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (S)-1-(1-Cyclopropyl-2-methoxy-ethyl)-5-(2,4-dichloro-phenyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (R)-1-(1-Cyclobutyl-ethyl)-5-(2,4-dichloro-phenyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (S)-1-(1-Cyclobutyl-ethyl)-5-(2,4-dichloro-phenyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (R)-1-(1-Cyclobutyl-propyl)-5-(2,4-dichloro-phenyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (S)-1-(1-Cyclobutyl-propyl)-5-(2,4-dichloro-phenyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (R)-5-(2-Chloro-5-fluoro-4-methoxy-phenyl)-1-(1-cyclopropyl-ethyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (S)-5-(2-Chloro-5-fluoro-4-methoxy-phenyl)-1-(1-cyclopropyl-ethyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (R)-5-(2-Chloro-5-fluoro-4-methoxy-phenyl)-1-(1-cyclopropyl-propyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (S)-5-(2-Chloro-5-fluoro-4-methoxy-phenyl)-1-(1-cyclopropyl-propyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (R)-5-(2-Chloro-5-fluoro-4-methoxy-phenyl)-1-(2-methoxy-1-methyl-ethyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (S)-5-(2-Chloro-5-fluoro-4-methoxy-phenyl)-1-(2-methoxy-1-methyl-ethyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (R)-5-(2-Chloro-5-fluoro-4-methoxy-phenyl)-1-(1-methoxymethyl-propyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (S)-5-(2-Chloro-5-fluoro-4-methoxy-phenyl)-1-(1-methoxymethyl-propyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (R)-5-(2-Chloro-5-fluoro-4-methoxy-phenyl)-1-(1-cyclopropyl-2-methoxy-ethyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (S)-5-(2-Chloro-5-fluoro-4-methoxy-phenyl)-1-(1-cyclopropyl-2-methoxy-ethyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (R)-5-(2-Chloro-5-fluoro-4-methoxy-phenyl)-1-(1-cyclobutyl-ethyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (S)-5-(2-Chloro-5-fluoro-4-methoxy-phenyl)-1-(1-cyclobutyl-ethyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (R)-5-(2-Chloro-5-fluoro-4-methoxy-phenyl)-1-(1-cyclobutyl-propyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (S)-5-(2-Chloro-5-fluoro-4-methoxy-phenyl)-1-(1-cyclobutyl-propyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (R)-1-(1-Cyclopropyl-ethyl)-5-(6-methoxy-2-methyl-pyridin-3-yl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (S)-1-(1-Cyclopropyl-ethyl)-5-(6-methoxy-2-methyl-pyridin-3-yl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (R)-1-(1-Cyclopropyl-propyl)-5-(6-methoxy-2-methyl-pyridin-3-yl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (S)-1-(1-Cyclopropyl-propyl)-5-(6-methoxy-2-methyl-pyridin-3-yl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (R)-1-(2-Methoxy-1-methyl-ethyl)-5-(6-methoxy-2-methyl-pyridin-3-yl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (S)-1-(2-Methoxy-1-methyl-ethyl)-5-(6-methoxy-2-methyl-pyridin-3-yl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (R)-1-(1-Methoxymethyl-propyl)-5-(6-methoxy-2-methyl-pyridin-3-yl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (S)-1-(1-Methoxymethyl-propyl)-5-(6-methoxy-2-methyl-pyridin-3-yl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (R)-1-(1-Cyclopropyl-2-methoxy-ethyl)-5-(6-methoxy-2-methyl-pyridin-3-yl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (S)-1-(1-Cyclopropyl-2-methoxy-ethyl)-5-(6-methoxy-2-methyl-pyridin-3-yl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (R)-1-(1-Cyclobutyl-ethyl)-5-(6-methoxy-2-methyl-pyridin-3-yl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (S)-1-(1-Cyclobutyl-ethyl)-5-(6-methoxy-2-methyl-pyridin-3-yl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (R)-1-(1-Cyclobutyl-propyl)-5-(6-methoxy-2-methyl-pyridin-3-yl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (S)-1-(1-Cyclobutyl-propyl)-5-(6-methoxy-2-methyl-pyridin-3-yl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (R)-1-(1-Cyclopropyl-ethyl)-5-(6-methoxy-2,5-dimethyl-pyridin-3-yl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (S)-1-(1-Cyclopropyl-ethyl)-5-(6-methoxy-2,5-dimethyl-pyridin-3-yl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (R)-1-(1-Cyclopropyl-propyl)-5-(6-methoxy-2,5-dimethyl-pyridin-3-yl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (S)-1-(1-Cyclopropyl-propyl)-5-(6-methoxy-2,5-dimethyl-pyridin-3-yl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (R)-5-(6-Methoxy-2,5-dimethyl-pyridin-3-yl)-1-(2-methoxy-1-methyl-ethyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (S)-5-(6-Methoxy-2,5-dimethyl-pyridin-3-yl)-1-(2-methoxy-1-methyl-ethyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (R)-5-(6-Methoxy-2,5-dimethyl-pyridin-3-yl)-1-(1-methoxymethyl-propyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (S)-5-(6-Methoxy-2,5-dimethyl-pyridin-3-yl)-1-(1-methoxymethyl-propyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (R)-1-(1-Cyclopropyl-2-methoxy-ethyl)-5-(6-methoxy-2,5-dimethyl-pyridin-3-yl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (S)-1-(1-Cyclopropyl-2-methoxy-ethyl)-5-(6-methoxy-2,5-dimethyl-pyridin-3-yl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (R)-1-(1-Cyclobutyl-ethyl)-5-(6-methoxy-2,5-dimethyl-pyridin-3-yl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (S)-1-(1-Cyclobutyl-ethyl)-5-(6-methoxy-2,5-dimethyl-pyridin-3-yl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (R)-1-(1-Cyclobutyl-propyl)-5-(6-methoxy-2,5-dimethyl-pyridin-3-yl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (S)-1-(1-Cyclobutyl-propyl)-5-(6-methoxy-2,5-dimethyl-pyridin-3-yl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (R)-1-(1-Cyclopropyl-ethyl)-5-(4-methoxy-2,5-dimethyl-phenyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (S)-1-(1-Cyclopropyl-ethyl)-5-(4-methoxy-2,5-dimethyl-phenyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (R)-1-(1-Cyclopropyl-propyl)-5-(4-methoxy-2,5-dimethyl-phenyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (S)-1-(1-Cyclopropyl-propyl)-5-(4-methoxy-2,5-dimethyl-phenyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (R)-5-(4-Methoxy-2,5-dimethyl-phenyl)-1-(2-methoxy-1-methyl-ethyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (S)-5-(4-Methoxy-2,5-dimethyl-phenyl)-1-(2-methoxy-1-methyl-ethyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (R)-5-(4-Methoxy-2,5-dimethyl-phenyl)-1-(1-methoxymethyl-propyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (S)-5-(4-Methoxy-2,5-dimethyl-phenyl)-1-(1-methoxymethyl-propyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (R)-1-(1-Cyclopropyl-2-methoxy-ethyl)-5-(4-methoxy-2,5-dimethyl-phenyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (S)-1-(1-Cyclopropyl-2-methoxy-ethyl)-5-(4-methoxy-2,5-dimethyl-phenyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (R)-1-(1-Cyclobutyl-ethyl)-5-(4-methoxy-2,5-dimethyl-phenyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (S)-1-(1-Cyclobutyl-ethyl)-5-(4-methoxy-2,5-dimethyl-phenyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (R)-1-(1-Cyclobutyl-propyl)-5-(4-methoxy-2,5-dimethyl-phenyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (S)-1-(1-Cyclobutyl-propyl)-5-(4-methoxy-2,5-dimethyl-phenyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (R)-1-(1-Cyclopropyl-ethyl)-5-(2,4-dimethoxy-pyrimidin-5-yl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (S)-1-(1-Cyclopropyl-ethyl)-5-(2,4-dimethoxy-pyrimidin-5-yl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (R)-1-(1-Cyclopropyl-propyl)-5-(2,4-dimethoxy-pyrimidin-5-yl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (S)-1-(1-Cyclopropyl-propyl)-5-(2,4-dimethoxy-pyrimidin-5-yl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (R)-5-(2,4-Dimethoxy-pyrimidin-5-yl)-1-(2-methoxy-1-methyl-ethyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (S)-5-(2,4-Dimethoxy-pyrimidin-5-yl)-1-(2-methoxy-1-methyl-ethyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (R)-5-(2,4-Dimethoxy-pyrimidin-5-yl)-1-(1-methoxymethyl-propyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (S)-5-(2,4-Dimethoxy-pyrimidin-5-yl)-1-(1-methoxymethyl-propyl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (R)-1-(1-Cyclopropyl-2-methoxy-ethyl)-5-(2,4-dimethoxy-pyrimidin-5-yl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (S)-1-(-Cyclopropyl-2-methoxy-ethyl)-5-(2,4-dimethoxy-pyrimidin-5-yl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (R)-1-(1-Cyclobutyl-ethyl)-5-(2,4-dimethoxy-pyrimidin-5-yl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (S)-1-(1-Cyclobutyl-ethyl)-5-(2,4-dimethoxy-pyrimidin-5-yl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (R)-1-(1-Cyclobutyl-propyl)-5-(2,4-dimethoxy-pyrimidin-5-yl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one; (S)-1-(1-Cyclobutyl-propyl)-5-(2,4-dimethoxy-pyrimidin-5-yl)-3-methyl-1H-pyrido[3,4-b]pyrazin-2-one.
 55. A composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
 56. A composition comprising a compound of claim 2 and a pharmaceutically acceptable carrier.
 57. A method of reducing symptoms caused by elevated levels of corticotropin releasing factor in a mammal comprising administering to said mammal a therapeutically effective amount of a compound of claim
 1. 58. A method of reducing symptoms caused by elevated levels of corticotropin releasing factor in a mammal comprising administering to said mammal a therapeutically effective amount of a compound of claim
 2. 59. A method of treating stress-related symptoms in a mammal comprising administering to said mammal a therapeutically effective amount of a compound of claim
 1. 60. A method of treating stress-related symptoms in a mammal comprising administering to said mammal a therapeutically effective amount of a compound of claim
 2. 61. A method of treating a disorder characterized by abnormal levels of corticotropin releasing factor in a mammal comprising administering to said mammal a therapeutically effective amount of a compound of claim
 1. 62. The method of claim 61 wherein said disorder is characterized by elevated levels of corticotropin releasing factor.
 63. A method of treating a disorder characterized by abnormal levels of corticotropin releasing factor in a mammal comprising administering to said mammal a therapeutically effective amount of a compound of claim
 2. 64. The method of claim 63 wherein said disorder is characterized by elevated levels of corticotropin releasing factor.
 65. A method of treating anxiety or depression in a mammal comprising administering to said mammal a therapeutically effective amount of a compound of claim
 1. 66. A method of treating anxiety or depression in a mammal comprising administering to said mammal a therapeutically effective amount of a compound of claim
 2. 67. A method of treating irritable bowel syndrome in a mammal comprising administering to said mammal a therapeutically effective amount of a compound of claim
 1. 68. A method of treating irritable bowel syndrome in a mammal comprising administering to said mammal a therapeutically effective amount of a compound of claim
 2. 